rs72658864
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_000527.5(LDLR):c.1733T>C(p.Val578Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V578F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1733T>C | p.Val578Ala | missense_variant | 12/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1733T>C | p.Val578Ala | missense_variant | 12/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251486Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135916
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461786Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 727190
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | - | ACMG categories: PM1,PM2,PP2,PP3,PP4,PP5,BP1 - |
Hypercholesterolemia, familial, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2021 | The p.V578A variant (also known as c.1733T>C), located in coding exon 12 of the LDLR gene, results from a T to C substitution at nucleotide position 1733. The valine at codon 578 is replaced by alanine, an amino acid with similar properties. In genome-wide association studies (GWAS) performed in a Sardinian population, this variant has been suggested to have some association with dyslipidemia risks (Sanna S et al. PLoS Genet, 2011 Jul;7:e1002198; Sidore C et al. Nat Genet, 2015 Nov;47:1272-1281). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at