Submissions for variant NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr)

dbSNP: rs879255066

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237476	SCV000295736	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237476	SCV000503429	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?)/software prediction damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237476	SCV000583903	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Iberoamerican FH Network	RCV000237476	SCV000748101	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001048311	SCV001212307	pathogenic	Familial hypercholesterolemia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 627 of the LDLR protein (p.Ala627Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 7903864, 9763532, 21376320, 23158915, 23375686, 25807990, 27206935, 27830735, 28235710, 28502510, 30108616). This variant is also known as p.Ala606Thr. ClinVar contains an entry for this variant (Variation ID: 252101). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 7903864). This variant disrupts the p.Ala627 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001048311	SCV001355020	pathogenic	Familial hypercholesterolemia	2023-07-18	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala606Thr in the mature protein) replaces alanine with threonine at codon 627 in the LDLR type B repeat 6 of the LDLR protein. 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). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 20538126, 23375686, 27206935, 27830735, 28235710, 30270083, 30400955, 34037665, 36226792, 37397863). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in several individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 7903864, 19020990, 25807990, 28502510, 36325061). This variant has been identified in 1/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Ala627Val and p.Ala627Asp, are considered to be disease-causing (ClinVar variation ID: 252102 and 226377), suggesting that alanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000237476	SCV001422631	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Ala627Thr variant in LDLR has been reported in 6 individuals with Familial Hypercholesterolemia (PMID: 7903864, 20538126, 27830735, 19020990, 28502510; Variation ID: 252101), segregated with disease in 2 affected relatives from 1 family and has been identified in 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs879255066). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 252101). In vitro functional studies provide some evidence that the p.Ala627Thr variant may slightly impact protein processing and binding affinity (PMID: 7903864). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3, PS4_Supporting (Richards 2015).
Ambry Genetics	RCV003352813	SCV004061836	pathogenic	Inborn genetic diseases	2023-09-28	criteria provided, single submitter	clinical testing	The c.1879G>A (p.A627T) alteration is located in coding exon 13 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1879, causing the alanine (A) at amino acid position 627 to be replaced by a threonine (T). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a heterozygous finding in numerous unrelated Asian individuals diagnosed with familial hypercholesterolemia (FH) (Cheng, 2023; Jiang, 2022; Jiang, 2015; Huang, 2022; Wang, 2020). This variant has also been reported in three unrelated Chinese patients with FH who were found to carry biallelic LDLR mutations. Two were compound heterozygotes and one was homozygous for the c.1879G>A variant (Ma, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477858	SCV004219962	pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251494 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in several individuals with Familial Hypercholesterolemia (FH) (PMID: 7903864 (1994), 9763532 (1998), 16092059 (2005), 28235710 (2017), (28502510 (2017), 30108616 (2018)). A functional study reported this variant was damaging to protein processing and binding (PMID: 7903864 (1994)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Department of Traditional Chinese Medicine, Fujian Provincial Hospital	RCV000237476	SCV002098051	likely pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research	The missense point mutations c.G1879A (p.A627T) in LDLR (NM_000527) was identified in a family with familial hypercholesterolemia. According to the American College of Medical Genetics and Genomics (ACMG) pathogenicity rating criteria and guidelines, it was predicted that the c.G1879A mutation was likely to be pathogenic. These mutations affected LDLR binding to LDL containing APOB and APOE, resulting in the disturbance of LDL metastasis in blood and excessive siltation in tissues, leading to multiple cutaneous xanthoma and atherosclerosis.