rs879254728
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.937T>C(p.Cys313Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C313W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.937T>C | p.Cys313Arg | missense_variant | 6/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.937T>C | p.Cys313Arg | missense_variant | 6/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3Uncertain:1
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5 (LDLR):c.937T>C (p.Cys313Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM1, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.978. PM1: Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases reported in PubMed: one case fulfil Simon Broome criteria for definite or possible FH in PMID 22881376, reported by Usifo et al, 2012, from British Heart Foundation Laboratories, University College London, UK; one case fulfil DLCN >=6 in PMID 19318025 reported by Alonso et al, 2009, from Lipid Clinic, Fundacion Jimenez Diaz, Spain. PS3 not met: Functional data is not available. PM5 not met: Three other missense variants at same codon: NM_000527.5 (LDLR):c.937T>G (p.Cys313Gly), ClinVarID 251538, is classified as Uncertain significance; NM_000527.5 (LDLR):c.939C>G (p.Cys313Trp), ClinVarID 251540, is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.938G>A (p.Cys313Tyr), ClinVarID 226339, is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at