Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000238489 | SCV002817124 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-08-29 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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: PM2 - PopMax MAF = 0.00009643 (0.009643%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.95. It is above 0.75, so PP3 is Met. |
LDLR- |
RCV000238489 | SCV000295749 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Ambry Genetics | RCV002411105 | SCV002722022 | likely pathogenic | Cardiovascular phenotype | 2016-05-05 | criteria provided, single submitter | clinical testing | The p.G636S variant (also known as c.1906G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1906. The glycine at codon 636 is replaced by serine, an amino acid with similar properties, and is located in the EGF precursor like domain. This alteration was reported in two individuals meeting clinical criteria for familial hypercholesterolemia (Damgaard et al. Atherosclerosis 2005;180(1):155-60; Brusgaard et al. Clin. Genet. 2006;69(3):277-83). Other alterations at the same amino acid position (also described as p.G615 in the literature), have been reported: p.G636D (c.1907G>A) and p.G636V (c.1907G>T) (Marduel et al. Hum. Mutat. 2010:31(11):E1811-24; Wang et al. PLoS ONE 2014;9(3):e92703). Based on data from ExAC, the A allele has an overall frequency of <0.01% (1/106207). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV003581635 | SCV004265556 | likely pathogenic | Familial hypercholesterolemia | 2023-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 636 of the LDLR protein (p.Gly636Ser). This variant is present in population databases (rs764550980, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 16542394). This variant is also known as G615S. ClinVar contains an entry for this variant (Variation ID: 252109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly615 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24671153). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |