Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000237820 | SCV001960909 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-06-07 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met. PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. |
LDLR- |
RCV000237820 | SCV000294915 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000237820 | SCV000322913 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | 0/190 non-FH alleles |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237820 | SCV000503224 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 , family member = 1 / Software predictions: Damaging |
Ambry Genetics | RCV002374397 | SCV002668237 | pathogenic | Cardiovascular phenotype | 2017-01-25 | criteria provided, single submitter | clinical testing | The p.C231W pathogenic mutation (also known as c.693C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 693. The cysteine at codon 231 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration, also referred to as C210W, has been reported in association with hypercholesterolemia (Marduel M et al. Hum Mutat. 2010;31:E1811-24; Norsworthy PJ et al. BMC Med Genet. 2014;15:70). In addition, multiple alterations at the same amino acid position have also been detected in individuals with familial hypercholesterolemia, including C231G (Sundvold H et al. Hum Mutat. 1996;7:70-1), C231R (Wang L et al. Nutr Metab Cardiovasc Dis. 2009;19:391-400) and C231Y (Shin JA et al. Clin Genet. 2000;57:225-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
All of Us Research Program, |
RCV000237820 | SCV004825852 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | clinical testing | This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 20809525, 24956927). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. This missense substitution occurs at an amino acid position that is known to be critical to protein structure/function. Other missense substitutions at this amino acid residue have been previously reported in individual(s) with disease and classified as pathogenic, which supports the functional importance of this position (PMID: 19073363, 27830735, 10422804, 11313767, 22698793). |