Submissions for variant NM_000527.5(LDLR):c.2206G>A (p.Val736Ile)

gnomAD frequency: 0.00001  dbSNP: rs547268730

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417287	SCV000503473	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/Software predictions: Benign
Color Diagnostics, LLC DBA Color Health	RCV000775613	SCV000909977	uncertain significance	Familial hypercholesterolemia	2023-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 736 of the LDLR protein. This variant is also known as p.Val715Ile in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 27497240; DOI: 10.1016/j.atherosclerosis.2013.07.011). This variant has been identified in 4/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192515	SCV001360709	uncertain significance	not specified	2019-02-06	criteria provided, single submitter	clinical testing	Variant summary: The variant, LDLR c.2206G>A (p.Val736Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277018 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2206G>A has been reported in the literature in individuals affected with familial hypercholesterolemia (Maurer_2016, Haralambos_2013). This report however, does not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001536350	SCV001753093	uncertain significance	not provided	2020-05-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar with conflicting interpretations of pathogenicity (ClinVar Variant ID#375835; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27497240)
All of Us Research Program, National Institutes of Health	RCV000417287	SCV004818509	uncertain significance	Hypercholesterolemia, familial, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 736 of the LDLR protein. This variant is also known as p.Val715Ile in the mature protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 27497240; DOI: 10.1016/j.atherosclerosis.2013.07.011). This variant has been identified in 4/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000417287	SCV005401000	uncertain significance	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	The observed missense c.2206G>A (p.Val736Ile) variant in LDLR gene has been reported previously in an individual affected with familial hypercholesterolemia (Maurer et al., 2016). The p.Val736Ile variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Benign/ Pathogenic/ Uncertain Significance (multiple submissions). Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid Val at position 736 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). In absence of another reportable variant in LDLR gene, the molecular diagnosis is not confirmed
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000417287	SCV000606615	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775613	SCV002086865	uncertain significance	Familial hypercholesterolemia	2020-03-18	no assertion criteria provided	clinical testing