ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.631C>G (p.His211Asp)

dbSNP: rs771917370
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238231 SCV000294833 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238231 SCV000322906 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Labcorp Genetics (formerly Invitae), Labcorp RCV005090212 SCV005838775 likely pathogenic Familial hypercholesterolemia 2024-02-10 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 211 of the LDLR protein (p.His211Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 17765246). ClinVar contains an entry for this variant (Variation ID: 251334). 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 with a positive predictive value of 95%. This variant disrupts the p.His211 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10570905, 17347910, 23064986, 27784735; Invitae). 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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