Submissions for variant NM_000527.5(LDLR):c.1867A>G (p.Ile623Val)

gnomAD frequency: 0.00013  dbSNP: rs555292896

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238541	SCV005328530	uncertain significance	Hypercholesterolemia, familial, 1	2023-01-27	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1867A>G (p.Ile623Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1 and PP1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: The supporting evidence is as follows: BS1: PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1). PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil.
LDLR-LOVD, British Heart Foundation	RCV000238541	SCV000295729	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000426889	SCV000520998	likely benign	not specified	2016-05-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000238541	SCV000689768	likely benign	Hypercholesterolemia, familial, 1	2017-09-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771171	SCV000752449	likely benign	Familial hypercholesterolemia	2025-02-02	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000238541	SCV000782929	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771171	SCV000903100	benign	Familial hypercholesterolemia	2018-06-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411101	SCV002721032	likely benign	Cardiovascular phenotype	2023-06-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000426889	SCV004848065	benign	not specified	2020-09-04	criteria provided, single submitter	clinical testing	The p.Ile623Val variant in LDLR is classified as benign. Although it has been reported in individuals with familial hypercholesterolemia or myocardial infarction (Kusters 2013 PMID:23833242, Cui 2019 PMID:30637778, Lee 2019 PMID:30971288), it has also been identified in 0.3% (71/19952) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Furthermore, 8 mammals harbor a valine (Val) at this position, despite high nearby conservation. ACMG/AMP criteria applied: BA1, BP4_Strong.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238541	SCV000606546	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000771171	SCV001461321	likely benign	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing