ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.947A>G (p.Asn316Ser)

gnomAD frequency: 0.00001  dbSNP: rs730882094
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237335 SCV000295105 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Color Diagnostics, LLC DBA Color Health RCV001176041 SCV001339858 likely pathogenic Familial hypercholesterolemia 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 316 of the LDLR protein. This variant is also known as p.Asn295Ser in the mature protein. This variant alters a conserved asparagine residue in the EGF-like repeat A of the LDLR protein (a.a. 315-354), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). This variant has been reported in ten individuals affected with familial hypercholesterolemia (PMID: 21376320, 28502495, 33994402). It has also been reported in two individuals affected with myocardial infarction (PMID: 25647241) and in an individual affected with coronary artery disease (PMID: 27050191). This variant has been identified in 6/282464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001176041 SCV003485865 uncertain significance Familial hypercholesterolemia 2022-06-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 316 of the LDLR protein (p.Asn316Ser). This variant is present in population databases (rs730882094, gnomAD 0.005%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 20538126). This variant is also known as N295S. ClinVar contains an entry for this variant (Variation ID: 183103). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161974 SCV000189549 not provided not provided no assertion provided in vitro

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