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

gnomAD frequency: 0.00006  dbSNP: rs201102461

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237176	SCV001960908	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000237176	SCV000267384	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-18	criteria provided, single submitter	reference population
LDLR-LOVD, British Heart Foundation	RCV000237176	SCV000294641	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	RCV000237176	SCV000503144	likely benign	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 / Software predictions: Conflicting
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237176	SCV000599327	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV000771221	SCV000903315	likely benign	Familial hypercholesterolemia	2021-03-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000237176	SCV000915812	likely pathogenic	Hypercholesterolemia, familial, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771221	SCV001225051	uncertain significance	Familial hypercholesterolemia	2021-10-21	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%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9399845, 11005141, 12417285, 15359125, 18718593, 28502495, 28932795, 29399563). This variant is also known as R94H. ClinVar contains an entry for this variant (Variation ID: 225402). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR 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.
GeneDx	RCV001788071	SCV002031099	uncertain significance	not provided	2024-04-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced protein expression and receptor activity (PMID: 12837857); Identified in multiple individuals with familial hypercholesterolemia (FH) (PMID: 32331935, 12417285); Reported to not segregate with disease in at least two families (PMID: 32252761); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.R94H or FH-Fukuoka; This variant is associated with the following publications: (PMID: 9399845, 21376320, 11005141, 20538126, 15359125, 15256764, 20599862, 18718593, 12837857, 34426522, 27821657, 30827231, 31491741, 32719484, 29399563, 28932795, 28502495, 29192238, 38308247, Al-Khateeb 2016[article], 35480308, 26632531, 37967952, 35538921, 38336686, 35534676, 33994402, 21146822, 34526433, 32331935, 12417285, 30583242, 34906454, 32252761)
Ambry Genetics	RCV002460059	SCV002618479	uncertain significance	Cardiovascular phenotype	2024-01-30	criteria provided, single submitter	clinical testing	The p.R115H variant (also known as c.344G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 344. The arginine at codon 115 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple East Asian familial hypercholesterolemia cohorts (Khoo KL et al. Clin. Genet. 2000;58:98-105; Yu W et al. Atherosclerosis. 2002;165:335-42; Kim JH et al. Mol. Cells. 2004;18:63-70; Chiou KR et al. Am. J. Cardiol. 2010;105:1752-8; Kim HN et al. Chonnam Med J. 2018;54:31-35; Tada H et al. J Clin Lipidol. 2018:397-402.e2). One functional study suggested this alteration leads to an approximately 35% reduction in both the amount of mature LDLR protein and LDLR activity compared to wildtype; however, the physiological relevance of this decrease is unclear (Chang JH et al. J. Lipid Res. 2003;44:1850-8). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.02% (48/276574) total alleles studied. The highest observed frequency was 0.23% (44/18844) of East Asian alleles. Based on data from the 2KJPN database, the population frequency in Japan is 0.39% (Yamaguchi-Kabata Y et al. J. Hum. Genet. 2018;63:213-230). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000237176	SCV002781787	uncertain significance	Hypercholesterolemia, familial, 1	2021-11-04	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000237176	SCV005416139	uncertain significance	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PS3_Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055742	SCV005726826	uncertain significance	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.344G>A (p.Arg115His; also described as R94H - FUKUOKA) results in a non-conservative amino acid change located in the LDL receptor-like module domain (IPR036055) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250682 control chromosomes, predominantly at a frequency of 0.0022 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.8 - fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013). c.344G>A has been reported in the literature in several heterozygous individuals of Asian origin affected with familial hypercholesterolemia (examples: Varret_1998, Khoo_2000, Yu_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Leigh_2017). The following publications have been ascertained in the context of this evaluation (PMID: 9399845, 11005141, 12417285, 15359125, 18718593, 28502495, 28932795, 29399563, 27821657). ClinVar contains an entry for this variant (Variation ID: 225402). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237176	SCV000606093	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000771221	SCV001456140	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing