Submissions for variant NM_000527.5(LDLR):c.1285G>T (p.Val429Leu)

dbSNP: rs28942078

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238117	SCV005375292	pathogenic	Hypercholesterolemia, familial, 1	2023-03-27	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1285G>T (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS1, PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.764. PM5: There is 1 missense variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G<A (p.Val429Met), ClinVar ID 3694. PS1: There is 1 missense variant in the same codon predicting the same amino acid change classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G>C (p.Val429Leu), ClinVar ID 226353. PP4: Variant meets PM2 and is identified in at least 1 index case meeting Simon Broome criteria for FH from PMID 9727746 (Nissen et al., 1998).
LDLR-LOVD, British Heart Foundation	RCV000238117	SCV000295343	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238117	SCV000782911	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519847	SCV003443162	likely pathogenic	Familial hypercholesterolemia	2022-11-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 9727746, 23021490, 32041611; Invitae). This variant is also known as V408L. ClinVar contains an entry for this variant (Variation ID: 251767). 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. Experimental studies have shown that this missense change affects LDLR function (PMID: 23021490, 25386756). This variant disrupts the p.Val429 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2569482, 11196104, 19837725, 21925660). 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 sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 429 of the LDLR protein (p.Val429Leu).
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	RCV000238117	SCV001467730	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research