chr19-11120197-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1951G>T(p.Asp651Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D651N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1951G>T | p.Asp651Tyr | missense_variant | 13/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1951G>T | p.Asp651Tyr | missense_variant | 13/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Mar 20, 2023 | 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. - |
Likely pathogenic, 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