rs879254457
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):c.284G>A(p.Cys95Tyr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C95G) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.284G>A | p.Cys95Tyr | missense_variant | 3/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.284G>A | p.Cys95Tyr | missense_variant | 3/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2
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 | - - |
Uncertain significance, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys95 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11139254, 11851376, 12417285, 15241806, 18718593, 19007590, 21955034, 23375686, 28235710, 28502510; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 251113). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 18096825, 19318025, 23375686, 28502510). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 95 of the LDLR protein (p.Cys95Tyr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at