Submissions for variant NM_000527.5(LDLR):c.1837G>A (p.Val613Ile)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV002051681	SCV000190310	uncertain significance	Hypercholesterolemia	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000210230	SCV000266314	likely benign	Hypercholesterolemia, familial, 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%
LDLR-LOVD, British Heart Foundation	RCV000210230	SCV000295691	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000210230	SCV000588610	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000771315	SCV000903571	likely benign	Familial hypercholesterolemia	2018-03-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771315	SCV000945773	uncertain significance	Familial hypercholesterolemia	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 613 of the LDLR protein (p.Val613Ile). This variant is present in population databases (rs148181903, gnomAD 0.007%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 16250003, 19837725). ClinVar contains an entry for this variant (Variation ID: 161288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LDLR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000210230	SCV001653367	uncertain significance	Hypercholesterolemia, familial, 1	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000210230	SCV003816523	uncertain significance	Hypercholesterolemia, familial, 1	2022-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700473	SCV005204650	uncertain significance	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1837G>A (p.Val613Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251438 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1837G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Fouchier_2005, Leigh_2008, Whittall_2010, Reijman_2023). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 18325082, 16250003, 19837725, 36752612). ClinVar contains an entry for this variant (Variation ID: 161288). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000210230	SCV000606532	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000771315	SCV002086854	uncertain significance	Familial hypercholesterolemia	2020-02-06	no assertion criteria provided	clinical testing