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SGBS1 is caused by damaging variants in the Glypican\u20103 (\n                    <jats:italic>GPC3<\/jats:italic>\n                    ) gene. The GPC3 protein plays a crucial role in cellular signaling processes including cell growth, embryogenesis, and differentiation. Functional maturation of GPC3 occurs via several steps of post\u2010translational modification (PTM) and processing to enable its transport to, and anchorage on, the plasma membrane. GPC3 positively modulates the canonical Wnt signaling pathways, while negatively regulating the Hedgehog signaling pathways. Loss\u2010of\u2010function is the underlying mechanism of disease for SGBS1, with a minority of reported pathogenic variants being missense substitutions. We report a family with four affected individuals in whom a novel\n                    <jats:italic>GPC3<\/jats:italic>\n                    missense variant was identified via exome sequencing: NM_004484.3: c.695C&gt;A; p.(Ala232Asp). The variant segregated with disease in the family, and functional studies conducted using HEK293T cells demonstrate a distinct mis\u2010localization of the mutant GPC3 protein, thereby supporting the pathogenicity of this novel missense variant. These findings allowed for an upgraded classification of the missense variant from a variant of uncertain significance to that of likely pathogenic.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64287","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T09:51:31Z","timestamp":1761126691000},"page":"632-641","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional Characterization of a Novel\n                    <i>GPC3<\/i>\n                    Missense Variant in Simpson\u2013Golabi\u2013Behmel Syndrome"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3445-3898","authenticated-orcid":false,"given":"Teresa","family":"Zhao","sequence":"first","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1032-8856","authenticated-orcid":false,"given":"Kirsten","family":"Allan","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4089-1886","authenticated-orcid":false,"given":"Juliet","family":"Taylor","sequence":"additional","affiliation":[{"name":"Genetic Health Service NZ (Northern Hub)  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7725-9470","authenticated-orcid":false,"given":"David R.","family":"Thorburn","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-634X","authenticated-orcid":false,"given":"Susan M.","family":"White","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8455-7778","authenticated-orcid":false,"given":"Tiong Y.","family":"Tan","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8431-0641","authenticated-orcid":false,"given":"John","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Sydney Medical School University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3339-7342","authenticated-orcid":false,"given":"Natalie B.","family":"Tan","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2048-3383","authenticated-orcid":false,"given":"David A.","family":"Stroud","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Biochemistry &amp; 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