19-11107484-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5_StrongPM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and 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: PM5_strong - Four more missense variants described in same codon, of which 2 variants classified as Pathogenic, so PM5_Strong is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.982. PP4 - Variant meets PM2. Identified in 1 FH case who fulfills Simon-Broome criteria for FH in PMID 1301940. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585188/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.910G>T | p.Asp304Tyr | missense_variant | Exon 6 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457672Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725092
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4
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subjects mutated among 2600 FH index cases screened = 2 , family members = 2 with co-segregation / previously described in association with FH / Software predictions: Damaging -
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The NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and 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: PM5_strong - Four more missense variants described in same codon, of which 2 variants classified as Pathogenic, so PM5_Strong is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.982. PP4 - Variant meets PM2. Identified in 1 FH case who fulfills Simon-Broome criteria for FH in PMID 1301940. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at