{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T21:35:59Z","timestamp":1761514559039,"version":"3.37.3"},"reference-count":11,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["H26-nanji-ippan-056; H30-nanji-ippan-003"],"award-info":[{"award-number":["H26-nanji-ippan-056; H30-nanji-ippan-003"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP17K08681"],"award-info":[{"award-number":["JP17K08681"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["16ek0210075h0001"],"award-info":[{"award-number":["16ek0210075h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center","award":["28-2-2"],"award-info":[{"award-number":["28-2-2"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center","award":["29-6-11"],"award-info":[{"award-number":["29-6-11"]}]},{"name":"Japan Heart Foundation & Astellas Grant"},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008880","name":"Kanae Foundation for the Promotion of Medical Science","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/501100008880","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Novartis Research Grants","award":["None"],"award-info":[{"award-number":["None"]}]},{"DOI":"10.13039\/501100005072","name":"Japanese Circulation Society","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/501100005072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Lipids Health Dis"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>We previously identified the c.344G\u2009&gt;\u2009A: p.(Arg115His) variant in the low-density lipoprotein receptor (<jats:italic>LDLR)<\/jats:italic>gene, which was interpreted as \u201cconflicting interpretations of pathogenicity\u201d in ClinVar, based on a genetic analysis of patients with familial hypercholesterolemia (FH). However, whether this variant affects the pathophysiology of FH remains unclear. Therefore, our aim was to annotate the c.344G\u2009&gt;\u2009A: p.(Arg115His) variant in the<jats:italic>LDLR<\/jats:italic>gene in FH. We present 2 families harboring the c.344G\u2009&gt;\u2009A: p.(Arg115His) variant in the<jats:italic>LDLR<\/jats:italic>gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genetic analyses were performed for the coding regions and the exon-intron boundary sequence of the<jats:italic>LDLR<\/jats:italic>and proprotein convertase subtilisin\/kexin type 9 (<jats:italic>PCSK9)<\/jats:italic>genes in 2 FH families. Next, the family without pathogenic variants in the<jats:italic>LDLR<\/jats:italic>and<jats:italic>PCSK9<\/jats:italic>genes was screened by whole-exome sequencing. Detailed clinical and biochemical data were gathered from family members.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In one family, the index case had biallelic c.1567G\u2009&gt;\u2009A: p.(Val523Met) and c.344G\u2009&gt;\u2009A: p.(Arg115His) variants in the<jats:italic>LDLR<\/jats:italic>gene, while the sibling had only the c.1567G\u2009&gt;\u2009A: p.(Val523Met) variant in the<jats:italic>LDLR<\/jats:italic>gene. There was no difference in the FH phenotype between the siblings. In another family, the index case and the sibling had no pathogenic variants in the<jats:italic>LDLR<\/jats:italic>,<jats:italic>PCSK9<\/jats:italic>, and apolipoprotein B (<jats:italic>APOB)<\/jats:italic>genes, but the sibling\u2019s wife with nonFH had the c.344G\u2009&gt;\u2009A: p.(Arg115His) variant in the<jats:italic>LDLR<\/jats:italic>gene. The sibling and his wife had 4 children, including an unaffected child and an affected child who had the c.344G\u2009&gt;\u2009A: p.(Arg115His) variant in the<jats:italic>LDLR<\/jats:italic>gene. In addition, the allele frequency of the c.344G\u2009&gt;\u2009A: p.(Arg115His) variant (0.0023\u20130.0043) in Japanese and East Asian populations is relatively high compared with that of the other<jats:italic>LDLR<\/jats:italic>pathogenic variants (0.0001\u20130.0008).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The c.344G\u2009&gt;\u2009A: p.(Arg115His) variant in the<jats:italic>LDLR<\/jats:italic>gene is interpreted as benign in individuals with FH.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12944-020-01252-4","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T13:03:32Z","timestamp":1586178212000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The benign c.344G &gt; A: p.(Arg115His) variant in the LDLR gene interpreted from a pedigree-based genetic analysis of familial hypercholesterolemia"],"prefix":"10.1186","volume":"19","author":[{"given":"Mika","family":"Hori","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheol","family":"Son","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatsune","family":"Ogura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariko","family":"Harada-Shiba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,6]]},"reference":[{"key":"1252_CR1","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.atherosclerosis.2010.11.005","volume":"214","author":"H Mabuchi","year":"2011","unstructured":"Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Tada H, et al. Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan. Atherosclerosis. 2011;214:404\u20137.","journal-title":"Atherosclerosis."},{"key":"1252_CR2","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1002\/humu.23634","volume":"39","author":"MA Iacocca","year":"2018","unstructured":"Iacocca MA, Chora JR, Carrie A, Freiberger T, Leigh SE, Defesche JC, et al. ClinVar database of global familial hypercholesterolemia-associated DNA variants. Hum Mutat. 2018;39:1631\u201340.","journal-title":"Hum Mutat"},{"key":"1252_CR3","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/S0021-9150(02)00249-6","volume":"165","author":"W Yu","year":"2002","unstructured":"Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H. Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. Atherosclerosis. 2002;165:335\u201342.","journal-title":"Atherosclerosis."},{"key":"1252_CR4","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.atherosclerosis.2019.08.004","volume":"289","author":"M Hori","year":"2019","unstructured":"Hori M, Ohta N, Takahashi A, Masuda H, Isoda R, Yamamoto S, et al. Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. Atherosclerosis. 2019;289:101\u20138.","journal-title":"Atherosclerosis."},{"key":"1252_CR5","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/jhg.2016.12","volume":"61","author":"K Higasa","year":"2016","unstructured":"Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, et al. Human genetic variation database, a reference database of genetic variations in the Japanese population. 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Each patient provided written informed consent to participate in the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All the participants provided written informed consent for the publication of the results of this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"62"}}