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

dbSNP: rs879255066

Total submissions: 12

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048311	SCV001212307	pathogenic	Familial hypercholesterolemia	2024-12-10	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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Ala606Thr. ClinVar contains an entry for this variant (Variation ID: 252101). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	likely pathogenic	Hypercholesterolemia, familial, 1	2024-08-05	criteria provided, single submitter	curation	The p.Ala627Thr variant in LDLR has been reported in >10 individuals with familial hypercholesterolemia (PMID: 25807990, 32759540, 34037665 7903864, 33994402, 20538126, 27830735, 19020990, 28502510; Variation ID: 252101), segregated with disease in 2 affected relatives from 1 family and has been identified in 0.004% (2/44880) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs879255066). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 252101) and has been interpreted as pathogenic/likely pathogenic by multiple submitters. 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. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Ala627Val and p.Ala627Asp, have been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 252102, 226377). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PP3_moderate, PM5_supporting, PS3_supporting, (Richards 2015).
Ambry Genetics	RCV004020971	SCV004061836	pathogenic	Cardiovascular phenotype	2024-06-18	criteria provided, single submitter	clinical testing	The p.A627T pathogenic mutation (also known as c.1879G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1879. The alanine at codon 627 is replaced by threonine, an amino acid with similar properties. This alteration, which is also known as p.A606T, has been reported in individuals with familial hypercholesterolemia (FH), including individuals with homozygous FH (Mak YT et al. Arterioscler Thromb Vasc Biol, 1998 Oct;18:1600-5; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Jiang L et al. J Clin Lipidol, 2016 Dec;10:538-546.e5; Xiang R et al. Atherosclerosis, 2017 Mar;258:84-88; Ma Y et al. J Clin Lipidol, 2018 Oct;12:230-235.e6; Huang CC et al. J Atheroscler Thromb, 2022 May;29:639-653; Jingxin S et al. Mol Genet Genomic Med, 2022 Dec;10:e2070; Cheng WZ et al. J Geriatr Cardiol, 2023 May;20:341-349). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000237476	SCV005399582	pathogenic	Hypercholesterolemia, familial, 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated low-density lipoprotein receptor repeat class B domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic or pathogenic, and is one of the most common pathogenic variants causing familial hypercholesterolaemia in Chinese populations (ClinVar, PMID: 30649024). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000237476	SCV005417065	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3+PS4+PP1+PP3_Moderate
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.