Submissions for variant NM_000527.5(LDLR):c.344G>A (p.Arg115His) (rs201102461)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center	RCV000237176	SCV000267384	uncertain significance	Familial hypercholesterolemia 1	2016-03-18	criteria provided, single submitter	reference population
LDLR-LOVD, British Heart Foundation	RCV000237176	SCV000294641	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	RCV000237176	SCV000503144	likely benign	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 / Software predictions: Conflicting
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237176	SCV000599327	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	curation
Color	RCV000771221	SCV000903315	uncertain significance	Familial hypercholesterolemia	2019-12-19	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000237176	SCV000915812	likely pathogenic	Familial hypercholesterolemia 1	2017-05-01	criteria provided, single submitter	clinical testing	The LDLR c.344G>A (p.Arg115His) missense variant has been reported in five studies and is found in a total of eight individuals with hypercholesterolemia, including one individual who carried the variant in a compound heterozygous state with a stop-gained variant and seven individuals who carried the variant in a heterozygous state (Khoo et al. 2000; Yu et al. 2002; Kim et al. 2004; Chiou et al. 2011; Mabuchi et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00234 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Arg115His variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000771221	SCV001225051	uncertain significance	Familial hypercholesterolemia	2019-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 115 of the LDLR protein (p.Arg115His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201102461, ExAC 0.2%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 9399845, 15359125, 29399563, 28502495, 18718593, 28932795, 11005141, 12417285). This variant is also known as R94H in the literature. ClinVar contains an entry for this variant (Variation ID: 225402). This variant has been reported to have conflicting or insufficient data to determine the effect on LDLR protein function (PMID: 12837857, 27821657). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237176	SCV000606093	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research