Submissions for variant NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn)

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237459	SCV000295458	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237459	SCV000322957	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/184 non-FH alleles; 0/100 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237459	SCV000503353	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with unclear co-segregation / previously described in association with FH/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000237459	SCV000540820	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237459	SCV000583835	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237459	SCV000588582	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000237459	SCV000607602	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Integrated Genetics/Laboratory Corporation of America	RCV000590270	SCV000697197	pathogenic	Familial hypercholesterolemia	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1474G>A (p.Asp492Asn) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/121480 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in multiple affected FH patients including heterozygous patients and compound heterozygous patients (Mak_1998, Chiou_2010, Bertolini_2013, Blaha_2015). Variant was shown to segregate with disease in at least one of the reported families (Blaha_2015). Variants involving nearby nucleotides such as c.1474G>C, c.1474delG, c.1475A>G, etc, have been reported in affected individuals suggesting variant of interest is located in a mutiaotn hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Robarts Research Institute,Western University	RCV000237459	SCV000782916	uncertain significance	Familial hypercholesterolemia 1	2018-01-02	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000237459	SCV000839982	likely pathogenic	Familial hypercholesterolemia 1	2017-04-26	criteria provided, single submitter	clinical testing	This c.1474G>A (p.Asp492Asn) variant has been reported in a 42 year old male patient with familial hypercholesterolemia from a cohort of 30 patients [reported as D471N, FH Graz-1 in PMID 9763532]. This variant was also reported in a patient presenting with a total cholesterol level of 23 mmol/L and xanthomas [PMID 25936317]; this patient also carried a second allele (p.Gly592Glu), which is classified as pathogenic by our laboratory . This variant was further detected in a patient from a cohort of 2,078 patients from Italy [PMID 23375686]; this patient also carried a p.Cys698Trp variant, classified as a variant of unknown significance by our laboratory at this time. Additional variants affecting the same amino acid at position 492 (p.Asp492Gly and p.Asp492His) have been reported in patients with familial hypercholesterolemia [PMID 16250003, 10208479].This variant was reported in 2 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/19-11224326-G-A). Asparagine at amino acid position 492 of the LDLR protein is highly conserved in mammals. While not validated for clinical use, the computer-based algorithms predict this p.Asp492Asn change to be deleterious. This variant is thus classified as likely pathogenic.
Color	RCV000590270	SCV000903572	likely pathogenic	Familial hypercholesterolemia	2019-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV000590270	SCV000939301	pathogenic	Familial hypercholesterolemia	2019-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 492 of the LDLR protein (p.Asp492Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs373646964, ExAC 0.003%). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 10230472). This variant has also been observed in several individuals with myocardial infarction (PMID: 25647241, 25487149) and many individuals with familial hypercholesterolemia (PMID: 9763532, 25936317, 20236128, 11005141, 23375686, 27680772, 22698793). This variant is also known as Asp471Asn and Graz-1. ClinVar contains an entry for this variant (Variation ID: 161285). A single experimental study showed that this missense change did not disrupt LDL uptake, but this has not been confirmed in additional studies (PMID: 25647241). This variant disrupts the p.Asp492 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related disease (PMID: 16250003, 10208479), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000237459	SCV001423554	pathogenic	Familial hypercholesterolemia 1	2020-03-10	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237459	SCV001428819	uncertain significance	Familial hypercholesterolemia 1	2019-03-20	criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000237459	SCV001432652	likely pathogenic	Familial hypercholesterolemia 1	2018-12-06	criteria provided, single submitter	research
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161989	SCV000189564	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV000148592	SCV000190307	uncertain significance	Hypercholesterolaemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237459	SCV000606438	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group,Broad Institute	RCV000237459	SCV001423102	pathogenic	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	curation	The p.Asp492Asn (p.Asp471Asn) variant in LDLR has been reported in at least 30 individuals (including 13 Italian, 3 Chinese, 2 Norwegian, 2 Taiwanese, 1 Czech, and 1 Saudi Arabian individuals) with Familial Hypercholesterolemia, segregated with disease in up to 14 affected relatives from up to 7 families (PMID: 25647241, 26748104, 29172679, 11737238, 17094996, 23375686, 11005141, 25936317, 15199436, 17539906, 20538126, 9763532, 21310417, 12436241, 19446849; DOI: 10.2217/clp.14.6), and has been identified in 0.01087% (2/18394) of East Asian chromosomes and 0.003518% (4/113704) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373646964). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of a homozygous individual with this variant is highly specific for Familial Hypercholesterolemia based on xanthomas and family history consistent with disease (DOI: 10.2217/clp.14.6). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on multiple reports in individuals with Familial Hypercholesterolemia and cosegregation with disease. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PP3, PP4 (Richards 2015).