rs879254606
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 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: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark.so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585029/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.642G>A | p.Trp214Ter | stop_gained | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.642G>A | p.Trp214Ter | stop_gained | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Dec 13, 2021 | The NM_000527.5(LDLR):c.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 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: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark. so PP4 is met. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 23, 2022 | The LDLR c.642G>A (p.Trp214*) nonsense variant causes the premature termination of LDLR protein synthesis. The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 16542394 (2006), 10532689 (1999)). Based on the available information, this variant is classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2018 | The p.W214* pathogenic mutation (also known as c.642G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 642. This changes the amino acid from a tryptophan to a stop codon within coding exon 4. This alteration has been reported in a familial hypercholesterolemia cohort (Jensen HK et al. Atherosclerosis. 1999 Oct;146:337-44 (reported as W193X)). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at