Submissions for variant NM_000527.5(LDLR):c.938_939delinsAT (p.Cys313Tyr)

dbSNP: rs875989910

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211591	SCV000295071	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000493281	SCV000582510	pathogenic	not provided	2017-11-29	criteria provided, single submitter	clinical testing	The c.938_939delGCinsAT variant in the LDLR gene results in the replacement of a Cysteine residue at amino acid position #313 with a Tyrosine residue (designated as C313Y). The c.938_939delGCinsAT substitution has been published previously (as C292Y due to alternative nomenclature) as a pathogenic variant associated with familial hypercholesterolemia (Lind et al., 1998). Based on the ACMG recommendations, c.938_939delGCinsAT is interpreted as a pathogenic variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000493281	SCV001433286	pathogenic	not provided	2020-03-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001804946	SCV002051995	likely pathogenic	Familial hypercholesterolemia	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 313 in the LDLR type A repeat 7 of the LDLR protein. This variant is also known as p.Cys292Tyr in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15556094; ClinVar SCV SCV000268590.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different DNA substitution with the same protein consequence, c.938G>A (p.Cys313Tyr), is known to be disease-causing (ClinVar variation ID: 226339). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001804946	SCV002147031	pathogenic	Familial hypercholesterolemia	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 313 of the LDLR protein (p.Cys313Tyr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with autosomal dominant familial hypercholesterolaemia (PMID: 9259195, 9698020, 22883975, 23680767). This variant is also known as C292Y. ClinVar contains an entry for this variant (Variation ID: 226338). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys313 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 19318025), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002372216	SCV002688724	pathogenic	Cardiovascular phenotype	2022-08-01	criteria provided, single submitter	clinical testing	The c.938_939delGCinsAT (p.C313Y) alteration, located in exon 6 (coding exon 6) of the LDLR gene, results from an in-frame deletion of GC and insertion of AT at nucleotide positions 938 to 939. This results in the substitution of the cysteine residue for a tyrosine residue at codon 313. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration (also called c.938_939del2ins2 and C292Y in published literature) has been reported in a female patient with a diagnosis of familial hypercholesterolemia (FH) (Lind, 1998). A single nucleotide substitution, c.938G>A, also resulting in p.C313Y has been reported in multiple patients with FH (Day, 1997; Thiart, 2000; Laurie, 2004; Vandrovcova, 2013; Martin, 2016). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR alterations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger, 2002). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Ambry internal data). Functional analysis demonstrated that the p.C313Y alteration had reduced LDLR function as compared to a normal control (Thiart, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407738	SCV004107015	likely pathogenic	LDLR-related disorder	2023-07-14	criteria provided, single submitter	clinical testing	The LDLR c.938_939delinsAT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in individuals with hypercholesterolaemia (legacy nomenclature p.Cys292Tyr; Lind et al. 1998. PubMed ID: 9698020; Benedek et al. 2021. PubMed ID: 33955087). In addition, an alternate nucleotide change leading to the same amino acid change, and three alternate amino acid changes at the p.Cys313 position (to Arg, Gly, and Trp) have been reported as causative in affected individuals (Leren and Bogsrud. 2021. PubMed ID: 33740630; Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000211591	SCV004175249	likely pathogenic	Hypercholesterolemia, familial, 1	2022-11-09	criteria provided, single submitter	clinical testing	The LDLR c.938_939delGCinsAT variant is classified as Likely Pathogenic (PM2, PM1, PP3, PP4) The LDLR c.938_939delGCinsAT variant is a deletion and insertion nucleotide change of two nucleotides in exon 6/18 of the LDLR gene, which is predicted to change the amino acid cysteine at position 313 in the protein to tyrosine. This variant is absent from population databases (PM2). This variant is located in the conserved LDL-receptor class A7 domain, and is an amino acid that has an effect both on folding and LDL binding (ClinGen Familial hypercholesterolaemia panel) (PM1). Computational predictions support a deleterious effect on the gene or gene product (PP3). The clinical features of this case are highly specific for a variant in the LDLR gene (Dutch lipid score 9) (PP4). The variant has been reported in dbSNP (rs875989910) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 226338). The variant, also know as Cys292Tyr, has been reported in a Swedish patient with familial hypercholesterolemia (PMID:9698020).
All of Us Research Program, National Institutes of Health	RCV000211591	SCV004833224	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-13	criteria provided, single submitter	clinical testing	This missense substitution due to either c.938_939delinsAT or c.938G>A has been reported in multiple individuals with familial hypercholesterolemia (FH) (PMID: 11040093, 15556094, 9259195, 27680772, 11810272, 22883975, 33269076, 9698020, 12052488). It occurs at an amino acid position that is known to be critical to protein structure/function. This variant is predicted to be deleterious by in silico analysis. This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Other missense substitutions at this amino acid residue have been previously reported in individuals with FH (PMID: 21382890, 22881376, 19318025, 15823288), which supports the functional importance of this position.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211591	SCV000268590	pathogenic	Hypercholesterolemia, familial, 1	2013-04-04	no assertion criteria provided	clinical testing