19-11102784-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM1PP4PP3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.311G>T (p.Cys104Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.0.0).PP3: REVEL = 0.882. PM1: Variant meets PM2 and alters Cys104, one of the cysteine residues listed. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH from PMID 16159606 (Graham et al., 2005), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584839/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.311G>T | p.Cys104Phe | missense_variant, splice_region_variant | Exon 3 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
The NM_000527.5(LDLR):c.311G>T (p.Cys104Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.0.0). PP3: REVEL = 0.882. PM1: Variant meets PM2 and alters Cys104, one of the cysteine residues listed. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH from PMID 16159606 (Graham et al., 2005), after alternative causes of high cholesterol were excluded. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at