Submissions for variant NM_000527.5(LDLR):c.920A>C (p.Asp307Ala)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003074992	SCV003461968	likely pathogenic	Familial hypercholesterolemia	2022-11-29	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 307 of the LDLR protein (p.Asp307Ala). This variant is not present in population databases (gnomAD no frequency). This variant disrupts the p.Asp307 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19717150, 28502510; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 28965616). 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.
All of Us Research Program, National Institutes of Health	RCV004808411	SCV005426477	uncertain significance	Hypercholesterolemia, familial, 1	2024-06-11	criteria provided, single submitter	clinical testing