chr19-11120197-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS3PM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1951G>T (p.Asp651Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2, PP3, and PP4 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: PS3: Level 1 assays: PMID 32937241: Heterologous cells (CHO) - results - 53% LDLR expression, 50% binding, and 80% uptake. Expression and binding are below 70% of wild-type, so functional study is consistent with damaging effect. PS3 is met.PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3: REVEL = 0.933. It is above 0.75, so PP3 is met. PP4: Variant meet PM2. PMID:16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH. So PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585693/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.1951G>T | p.Asp651Tyr | missense_variant | Exon 13 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
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The NM_000527.5(LDLR):c.1951G>T (p.Asp651Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2, PP3, and PP4 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: PS3: Level 1 assays: PMID 32937241: Heterologous cells (CHO) - results - 53% LDLR expression, 50% binding, and 80% uptake. Expression and binding are below 70% of wild-type, so functional study is consistent with damaging effect. PS3 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3: REVEL = 0.933. It is above 0.75, so PP3 is met. PP4: Variant meet PM2. PMID: 16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH. So PP4 is met. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at