ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.398A>C (p.Asp133Ala)

gnomAD frequency: 0.00001  dbSNP: rs1317204420
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000700653 SCV000829417 pathogenic Familial hypercholesterolemia 2025-01-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 133 of the LDLR protein (p.Asp133Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with LDLR-related conditions (internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 577814). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264550 SCV001442757 uncertain significance not specified 2020-10-08 criteria provided, single submitter clinical testing Variant summary: LDLR c.398A>C (p.Asp133Ala) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 258698 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.398A>C in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002485721 SCV002778052 uncertain significance Hypercholesterolemia, familial, 1 2021-10-06 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV002485721 SCV005426444 uncertain significance Hypercholesterolemia, familial, 1 2024-07-10 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with alanine at codon 133 of the LDLR protein. This variant is also known as p.Asp112Ala in the mature protein. This variant alters a conserved aspartic acid residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Asp133Asn, is considered to be disease-causing (ClinVar variation ID: 251202), suggesting that aspartic acid at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Natera, Inc. RCV000700653 SCV001456142 uncertain significance Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing

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