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

gnomAD frequency: 0.00001  dbSNP: rs121908033

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003924	SCV000294768	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	RCV000003924	SCV000503175	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000003924	SCV000782949	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 175 of the LDLR protein (p.Asp175Asn). This variant is present in population databases (rs121908033, gnomAD 0.01%). This missense change has been observed in individuals with familial combined hyperlipidemia and/or familial hypercholesterolemia (FH) (PMID: 2565980, 2799589, 3430554, 7773731, 24014831, 26342331). It has also been observed to segregate with disease in related individuals. This variant is also known as FH Afrikaner-3, FH3 and p.Asp154Asn. ClinVar contains an entry for this variant (Variation ID: 3726). 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. Experimental studies have shown that this missense change affects LDLR function (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	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090451	SCV001246004	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000003924	SCV001423090	pathogenic	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	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).
3billion	RCV000003924	SCV002521080	pathogenic	Hypercholesterolemia, familial, 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003726). A different missense changes at the same codon (p.Asp175Tyr) has been reported to be associated with LDLR related disorder (ClinVar ID: VCV000251278 ). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002336075	SCV002645016	pathogenic	Cardiovascular phenotype	2023-12-13	criteria provided, single submitter	clinical testing	The c.523G>A (p.D175N) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 523, causing the aspartic acid (D) at amino acid position 175 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/251312) total alleles studied. The highest observed frequency was 0.011% (2/18386) of East Asian alleles. This mutation has been found to be a common pathogenic alteration in different South African hypercholesterolemia population cohorts (Kotze, 1989; Kotze, 1991; Graadt van Roggen, 1991), with haplotype analysis indicating that it is a founder mutation (Loubser, 1999). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis indicates that this variant, which impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 4, is expected to have a deleterious impact on protein function (Jeon, 2005; Ambry internal data). In vitro functional studies suggest that this alteration (also referred to as p.D154N) causes deficient LDLR function via reduced expression and a decrease in this receptor's affinity for LDL compared to wildtype (Graadt van Roggen, 1995). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001090451	SCV004168475	pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect through the formation of LDL receptors that are defective in their ability to bind LDL (Graadt van Roggen et al., 1995); Reported as a founder mutation in the South African population; also known as FH Afrikaner-3, FH3 and p.Asp154Asn (Kotze et al., 1987; Graadt van Roggen et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 3430554, 7773731, 34037665, 2799589, 10422804, 32041611, 26342331, 24014831)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000003924	SCV004848514	pathogenic	Hypercholesterolemia, familial, 1	2020-12-08	criteria provided, single submitter	clinical testing	The p.Asp175Asn variant in LDLR (also described as known as FH-3 alleles and p.Asp154Asn in the literature) is considered to be a founder variant in South Africa, that has been reported in multiple individuals with familial cholesterolemia (FH) and their affected relatives (Kotze 1987 PMID: 3430554, Kotze 1991 PMID: 1952806, Graadt van Roggen 1991 PMID: 1757095, Graadt van Roggen 1995 PMID: 7773731, Vergotine 2001 PMID: 11845603, Stein 2013 PMID: 24014831). This variant has also been reported by other clinical laboratories in ClinVar (Variantion ID: 3726) and has been identified in 0.01% (2/18386) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function by reducing LDLR activity (Graadt van Roggen 1995 PMID: 7773731) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_supporting, PP3.
OMIM	RCV000003924	SCV000024089	pathogenic	Hypercholesterolemia, familial, 1	1991-12-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003924	SCV000268568	pathogenic	Hypercholesterolemia, familial, 1	2015-01-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003924	SCV000606147	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research