Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV003582733 | SCV004309437 | pathogenic | Familial hypercholesterolemia | 2023-07-14 | criteria provided, single submitter | clinical testing | This variant is also known as N407K. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 428 of the LDLR protein (p.Asn428Lys). This variant is not present in population databases (gnomAD no frequency). A different variant (c.1284C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 11005141, 11238294, 11668640, 11857755; Invitae). This suggests that this variant is also likely to be causative of disease. 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. For these reasons, this variant has been classified as Pathogenic. |
Color Diagnostics, |
RCV003582733 | SCV004358520 | likely pathogenic | Familial hypercholesterolemia | 2023-01-17 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Asn407Lys in the mature protein) replaces asparagine with lysine at codon 428 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). However, a different nucleotide change resulting in the same protein consequence (c.1284C>G) is reported to be disease-causing (ClinVar variation ID: 251766), suggesting that this variant under investigation (c.1284C>A) may also be disease-causing. Based on the available evidence, this variant is classified as Likely Pathogenic. |