Submissions for variant NM_000527.5(LDLR):c.1966C>A (p.His656Asn)

gnomAD frequency: 0.00001  dbSNP: rs762815611

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237688	SCV001960935	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-18	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1966C>A (p.His656Asn) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS3, PP1_Strong, PM2, PP3 and PP4) 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: BS3 - PMID: 32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). ---- functional study is consistent with no damaging effect. PP1_strong - 1 family with 6 informative meiosis is reported by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - PopMax MAF = 0.00002638 (0.0026%) in European non-Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,905. PP4 - Variant meets PM2. Variant is reported in 1 index case fulfills Simon-Broome criteria.
LDLR-LOVD, British Heart Foundation	RCV000237688	SCV000295782	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237688	SCV000322993	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237688	SCV000503441	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family members = 5 with co-segregation / previously described in association with FH
Fundacion Hipercolesterolemia Familiar	RCV000237688	SCV000607659	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242724	SCV001415830	pathogenic	Familial hypercholesterolemia	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 656 of the LDLR protein (p.His656Asn). This variant is present in population databases (rs762815611, gnomAD 0.004%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 15823288, 20828696, 21382890, 23375686). This variant is also known as H635N. ClinVar contains an entry for this variant (Variation ID: 252136). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.His656 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11737238), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237688	SCV001429019	uncertain significance	Hypercholesterolemia, familial, 1	2019-07-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002418057	SCV002718911	likely pathogenic	Cardiovascular phenotype	2016-05-13	criteria provided, single submitter	clinical testing	The p.H656N variant (also known as c.1966C>A), located in coding exon 13 of the LDLR gene, results from a C to A substitution at nucleotide position 1966. The histidine at codon 656 is replaced by asparagine, an amino acid with similar properties, and is located in the EGF precursor-like domain. This variant, also referred to as p.H635N, has been reported in unrelated individuals reported to have familial hypercholesterolemia (Mozas P et al. Hum Mutat. 2004:24(2):187; Damgaard D et al. Atherosclerosis. 2005;180(1):155-60; van der Graaf A et al. Circulation. 2011;123(11):1167-73; Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant was also reported in a myocardial infarction-free control group, though clinical details were limited (Do R et al. Nature. 2015;518(7537):102-6). A study using surface plasmon resonance spectroscopy showed that this variant results in altered binding for substrate at low pH (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another alteration affecting this amino acid (p.H656Q, c.1968C>G) has been reported in association with hypercholesterolemia (Descamps OS et al. Eur J Clin Invest. 2001;31(11):958-65 (reported as p.H635Q)). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. Based on data from ExAC, the A allele has an overall frequency of <0.01% (2/106164). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000237688	SCV004824113	uncertain significance	Hypercholesterolemia, familial, 1	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant (also known as p.His635Asn in the mature protein) replaces histidine with asparagine at codon 656 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not have a significant impact on LDLR binding activity (PMID: 32015373). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15241806, 15823288, 20828696, 23375686, 33418990). It has also been reported in individuals with suspected familial hypercholesterolemia (PMID: 21382890, 33955087). This variant has been identified in 3/251440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237688	SCV000606564	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786344	SCV000925122	likely pathogenic	not provided	2016-08-16	no assertion criteria provided	provider interpretation	The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: p.His656Asn (c.1966C>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as likely pathogenic. Given sufficient case data and functional studies, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is strong case data. Mozas P et al. Hum Mutat. 2004:24(2):187, reported this variant in one individual and predicted that the basic to neurtral amino acid change could be expected to alter the conformation of the protein and, therefore, to prevent the transport to the Golgi apparatus of the misfolded LDLR. This article reports the variant as p.H635N Damgaard D et al. Atherosclerosis. 2005;180(1):155-60 reported this variant as novel in two individuals of a large FH cohort. They did not provide additional phenotype details. This article reports the variant as p.H635N van der Graaf A et al. Circulation. 2011;123(11):1167-73 reported this variant in a pediatric individual who presented with familial hypercholesterolemia. They did not provide additional phenotypic details. Bertolini et al. Atherosclerosis. 2013 Apr;227(2):342-8 reported this variant in their cohort of FH patients, but supplemental figures are unavailable. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The histadine at codon 656 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at the same codon (p.H635Q). A study using surface plasmon resonance spectroscopy showed that this variant results in altered binding for substrate at low pH (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another alteration affecting this amino acid (p.H656Q, c.1968C>G) has been reported in association with hypercholesterolemia (Descamps OS et al. Eur J Clin Invest. 2001;31(11):958-65 (reported as p.H635Q)). There are two individuals with variation at codon 656 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 16, 2016).