Submissions for variant NM_000527.5(LDLR):c.523G>A (p.Asp175Asn) (rs121908033)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003924	SCV000294768	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	RCV000003924	SCV000503175	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1, family member =1 /FH-Afrikaner-3 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003924	SCV000583693	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Robarts Research Institute,Western University	RCV000003924	SCV000782949	likely pathogenic	Familial hypercholesterolemia 1	2018-01-02	criteria provided, single submitter	clinical testing
Color	RCV000775043	SCV000909140	pathogenic	Familial hypercholesterolemia	2018-08-13	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This missense variant (also known as p.Asp154Asn in the mature protein and as FH Afrikaner-3) is located in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that this variant causes significant defect in the LDLR activity (PMID: 7773731). This variant has been reported in numerous Afrikaner individuals affected with familial hypercholesterolemia and is thought to be a founder mutation in that population (PMID: 2799589, 9727745). This variant is rare in the general population and has been identified in 2/246152 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Invitae	RCV000775043	SCV000951227	pathogenic	Familial hypercholesterolemia	2018-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 175 of the LDLR protein (p.Asp175Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with familial combined hyperlipidemia, familial hypercholesterolemia (FH) and has been shown to segregate with disease in FH families (PMID: 26342331, 2799589, 3430554, 2565980, 7773731, 24014831). This variant is also known as FH Afrikaner-3, FH3 and p.Asp154Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 3726). Experimental studies have shown that this missense change causes a deleterious effect on LDL binding ability and reduced LDLR cell surface expression (PMID: 7773731). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000003924	SCV000987518	pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001090451	SCV001246004	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
OMIM	RCV000003924	SCV000024089	pathogenic	Familial hypercholesterolemia 1	1991-12-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003924	SCV000268568	pathogenic	Familial hypercholesterolemia 1	2015-01-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003924	SCV000606147	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group,Broad Institute	RCV000003924	SCV001423090	pathogenic	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	curation	The p.Asp175Asn variant in LDLR has been reported in over 15 individuals with Familial Hypercholesterolemia, segregated with disease in 10 affected relatives from 2 families (PMID: 1757095,11845603, 2799589; DOI: 10.4172/2327-5790.1000167), and has been identified in 0.01088% (2/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908033). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant is a known founder variant in South Africa (PMID: 1757095). This variant has also been reported as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 3726). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based on the number of affected probands with the varianht and the segregation of this variant with FH. ACMG/AMP Criteria applied: PS4, PP1_strong, PP3 (Richards 2015).