rs875989910

chr19-11107512-GC-AT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):c.938_939delinsAT(p.Cys313Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C313R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.87

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11107511-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251537.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-11107512-GC-AT is Pathogenic according to our data. Variant chr19-11107512-GC-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.938_939delinsAT	p.Cys313Tyr	missense_variant, splice_region_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.938_939delinsAT	p.Cys313Tyr	missense_variant, splice_region_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 09, 2022	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). -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 04, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 13, 2023	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. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 13, 2020	- -

Familial hypercholesterolemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	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. -

LDLR-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 14, 2023

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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs875989910; hg19: chr19-11218188;