rs761765254
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) 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 - PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.787.It is above 0.75, so PP3 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585200/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.932A>C | p.Lys311Thr | missense_variant | Exon 6 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152064Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000350 AC: 51AN: 1456158Hom.: 0 Cov.: 32 AF XY: 0.0000290 AC XY: 21AN XY: 724384
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74280
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) 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 - PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.787. It is above 0.75, so PP3 is Met. -
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not provided Pathogenic:1Uncertain:1
PP3, PM2, PM3_strong -
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Familial hypercholesterolemia Pathogenic:1Uncertain:1
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This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 311 of the LDLR protein (p.Lys311Thr). This variant is present in population databases (rs761765254, gnomAD 0.007%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15556094). This variant is also known as p.K290T. ClinVar contains an entry for this variant (Variation ID: 251531). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at