Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000238519 | SCV002506375 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-12-13 | reviewed by expert panel | curation | 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. |
| LDLR- |
RCV000238519 | SCV000294839 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV002365240 | SCV002657410 | pathogenic | Cardiovascular phenotype | 2018-01-16 | criteria provided, single submitter | clinical testing | 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003477849 | SCV004219990 | pathogenic | not provided | 2022-12-23 | criteria provided, single submitter | clinical testing | 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. |