ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser)

gnomAD frequency: 0.00001  dbSNP: rs764550980
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel 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-LOVD, British Heart Foundation 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.

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