Submissions for variant NM_000527.5(LDLR):c.1836C>A (p.Ala612=)

dbSNP: rs143872778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000508762	SCV004022370	uncertain significance	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1836C>A (p.Ala612=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD v2.1.1). Frequency is higher in "other" population exomes and genomes but number of allele is below 10000 BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001188069	SCV000627023	likely benign	Familial hypercholesterolemia	2024-11-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188069	SCV001355015	likely benign	Familial hypercholesterolemia	2017-07-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413394	SCV002716331	likely benign	Cardiovascular phenotype	2022-05-16	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330735	SCV004037851	likely benign	not specified	2023-08-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000508762	SCV004822507	likely benign	Hypercholesterolemia, familial, 1	2024-02-05	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508762	SCV000606530	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001188069	SCV002086852	uncertain significance	Familial hypercholesterolemia	2019-10-28	no assertion criteria provided	clinical testing