ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1403T>A (p.Val468Asp)

dbSNP: rs879254890
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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 RCV000237869 SCV004022476 uncertain significance Hypercholesterolemia, familial, 1 2023-04-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.1403T>A (p.Val468Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.823 PP4 - Variant meet PM2. PMID: 20828696 (Medeiros et al., 2010), 1 case who fulfills Simon-Broome criteria for FH, after alternative causes of high cholesterol have been excluded.
LDLR-LOVD, British Heart Foundation RCV000237869 SCV000295413 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237869 SCV000322949 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles
Invitae RCV003581624 SCV004298357 likely pathogenic Familial hypercholesterolemia 2023-11-06 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 468 of the LDLR protein (p.Val468Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of LDLR-related conditions (PMID: 20828696; Invitae). ClinVar contains an entry for this variant (Variation ID: 251828). 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%. 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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