Submissions for variant NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr) (rs879255066)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237476	SCV000295736	likely pathogenic	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Iberoamerican FH Network	RCV000237476	SCV000748101	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001048311	SCV001212307	pathogenic	Familial hypercholesterolemia	2019-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 627 of the LDLR protein (p.Ala627Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of familial hypercholesterolemia (PMID: 7903864, 27830735, 9763532, 25807990, 23375686, 23158915, 27206935, 30108616, 28235710, 21376320, 28502510). This variant is also described as p.Ala606Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 252101). This variant has been reported to affect LDLR protein 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	RCV001048311	SCV001355020	likely pathogenic	Familial hypercholesterolemia	2019-06-06	criteria provided, single submitter	clinical testing
Broad Institute Rare Disease Group,Broad Institute	RCV000237476	SCV001422631	uncertain significance	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	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).