Submissions for variant NM_000527.5(LDLR):c.1284C>A (p.Asn428Lys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003582733	SCV004309437	pathogenic	Familial hypercholesterolemia	2024-03-04	criteria provided, single submitter	clinical testing	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. This variant is also known as N407K. 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%. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003582733	SCV005900632	likely pathogenic	Familial hypercholesterolemia	2024-10-25	criteria provided, single submitter	clinical testing	This variant is also known as c.1221C>G (p.Asn407Lys) by legacy nomenclature. The c.1284C>A (p.Asn428Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in individuals with familial hypercholesterolemia (PMID: 11005141, 11668640, 11845603, 11857755, 14508510, 15556094, 21382890, 35047021, 36499307). The c.1284C>A (p.Asn428Lys) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.0002% (3/1613996) and thus is presumed to be rare. Based on the available evidence, c.1284C>A (p.Asn428Lys) is classified as Likely Pathogenic.