Submissions for variant NM_000527.5(LDLR):c.1545C>T (p.Asn515=)

gnomAD frequency: 0.00183  dbSNP: rs147896205

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237272	SCV000295489	benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000237272	SCV000410534	likely benign	Hypercholesterolemia, familial, 1	2017-04-27	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771546	SCV000752431	benign	Familial hypercholesterolemia	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771546	SCV000904107	benign	Familial hypercholesterolemia	2017-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193181	SCV001361869	benign	not specified	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1545C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 251392 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. c.1545C>T has been reported in the literature in sequencing studies of individuals affected with Familial Hypercholesterolemia (Sharifi_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001706281	SCV001887428	benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26892515)
Ambry Genetics	RCV002401936	SCV002706285	likely benign	Cardiovascular phenotype	2019-02-25	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.
CeGaT Center for Human Genetics Tuebingen	RCV001706281	SCV003918063	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	LDLR: BP4, BP7
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001706281	SCV004219951	benign	not provided	2023-06-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000237272	SCV004822473	benign	Hypercholesterolemia, familial, 1	2024-01-11	criteria provided, single submitter	clinical testing