rs875989910
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000527.5(LDLR):c.938_939delGCinsAT(p.Cys313Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C313G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.938_939delGCinsAT | p.Cys313Tyr | missense_variant, splice_region_variant | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4
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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). -
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. -
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Familial hypercholesterolemia Pathogenic:2
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: 9698020; 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. -
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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. 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. -
Dyslipidemia Pathogenic:1
PS4, PM1, PM2, PP3, PP4 -
LDLR-related disorder Pathogenic:1
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 hypercholesterolemia (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 (Van Leuven et al. 2001. PubMed ID: 11257257; Leren and Bogsrud. 2021. PubMed ID: 33740630; Arrobas Velilla et al. 2022. PubMed ID: 36105085). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as likely pathogenic. -
not provided Pathogenic:1
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. -
Cardiovascular phenotype Pathogenic:1
The c.938_939delGCinsAT pathogenic mutation (also known as p.C313Y), located in 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, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations 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 L. Hum Mutat. 2002;20(2):81-7). This variant, also referred to as p.C292Y, and a single nucleotide substitution resulting in the same amino acid change (p.C313Y, c.938G>A) was reported in individual(s) with features consistent with FH (Lind et al. J Intern Med. 1998;244(1):19-25; Thiart et al. Mol Cell Probes. 2000;14(5):299-304; Day et al. Hum Mutat.1997;10(2):116-27; Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Vandrovcova J et al. Genet Med, 2013 Dec;15:948-57; Martin R et al. Atherosclerosis, 2016 11;254:8-13). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 7 (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at