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The aim of this study was to explore the molecular mechanism of <jats:italic>LDLR<\/jats:italic> c.501C&gt;A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of <jats:italic>LDLR<\/jats:italic> variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>All members of the two families with the <jats:italic>LDLR<\/jats:italic> c.501C&gt;A variant showed high levels of LDLC. The relationship between the clinical phenotype and <jats:italic>LDLR<\/jats:italic> variants was confirmed in the current study. Both <jats:italic>in silico<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> analyses showed that <jats:italic>LDLR<\/jats:italic> c.501C&gt;A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the\u00a0PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p><jats:italic>LDLR<\/jats:italic> c.501C&gt;A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with <jats:italic>LDLR<\/jats:italic> c.501C&gt;A variant.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12944-021-01536-3","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T13:03:46Z","timestamp":1631451826000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The LDLR c.501C&gt;A is a disease-causing variant in familial hypercholesterolemia"],"prefix":"10.1186","volume":"20","author":[{"given":"Haochang","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruoyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingchu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaoyi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0547-3045","authenticated-orcid":false,"given":"Xiaomin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,9,12]]},"reference":[{"key":"1536_CR1","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1172\/JCI200318925","volume":"111","author":"DJ Rader","year":"2003","unstructured":"Rader DJ, Cohen J, Hobbs HH. 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