Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237335 | SCV000295105 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Color Diagnostics, |
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. |
RCV000161974 | SCV000189549 | not provided | not provided | no assertion provided | in vitro |