Submissions for variant NM_000527.5(LDLR):c.2120A>T (p.Asp707Val)

dbSNP: rs879255143

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237572	SCV000295882	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237572	SCV000484742	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237572	SCV000503465	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation/software prediction damaging
GeneDx	RCV000521276	SCV000617512	likely pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic was identified in the LDLR gene. The D707V variant has been reported in association with FH (Marduel et al., 2010; Wang et al., 2016). The D707V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D707V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, while missense variants in the same residue (D707N, D707Y) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258046	SCV001434875	likely pathogenic	Familial hypercholesterolemia	2019-10-30	criteria provided, single submitter	clinical testing	The c.2120A>T (p.Asp707Val) variant in the LDLR gene has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 20809525, 27765764) and is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Asp707Val change to be deleterious. In addition, missense variants in the same amino acid residue (p.Asp707Asn and p.Asp707Tyr) have also been reported in affected individuals with FH (PMID: 22881376, 19318025). Therefore, this c.2120A>T (p.Asp707Val) variant in the LDLR gene is classified as likely pathogenic.
deCODE genetics, Amgen	RCV000237572	SCV004022250	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-21	no assertion criteria provided	research	The variant NM_000527.5:c.2120A>T (chr19:11120502) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.53, P= 8.17e-06), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 2.31, P= 3.79e-05), pure hypercholesterolaemia using 1515 cases and 283197 controls (OR= 84.06, P= 3.36e-04) and myocardial infarction using 25692 cases and 320832 controls (OR= 56.16, P= 1.36e-03). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5_Strong) this variant classifies as likely pathogenic.