Submissions for variant NM_000527.5(LDLR):c.1056C>T (p.Cys352=)

gnomAD frequency: 0.00026  dbSNP: rs13306515

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082978	SCV000556792	benign	Familial hypercholesterolemia	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000462425	SCV000689754	benign	Hypercholesterolemia, familial, 1	2017-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780374	SCV000917576	likely benign	not specified	2017-09-22	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1056C>T (p.Cys352Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 222/276416 control chromosomes from all ethnicities, but was observed predominantly in the East Asian subpopulation at a frequency of 0.008694 (164/18864). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been identified in patients reported in the literature without strong evidence for causality. In addition, the variant has been found to co-occur with a pathogenic LDLR mutation in a patient (c.259G>T/p.W66G), supporting a benign outcome for the variant of interest (Jensen_1996). One clinical diagnostic laboratory has classified this variant as benign. Taken together, this variant is classified as likely benign, until additional studies become available (ie, clinical and/or functional studies).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858795	SCV001134246	benign	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000462425	SCV001285934	uncertain significance	Hypercholesterolemia, familial, 1	2019-03-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV000780374	SCV002064929	likely benign	not specified	2019-03-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402326	SCV002714712	likely benign	Cardiovascular phenotype	2016-11-02	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858795	SCV003799774	likely benign	not provided	2022-04-11	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000462425	SCV000606303	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research