rs879255072
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.939.It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 1 index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID:20809525), so PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585679/MONDO:0007750/013
Frequency
Consequence
ENST00000558518.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1907G>A | p.Gly636Asp | missense_variant | 13/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1907G>A | p.Gly636Asp | missense_variant | 13/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Aug 29, 2022 | The NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.939. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 1 index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID: 20809525), so PP4 is Met. - |
Uncertain significance, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at