Submissions for variant NM_000527.5(LDLR):c.514G>A (p.Asp172Asn)

gnomAD frequency: 0.00003  dbSNP: rs879254554

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238587	SCV000294756	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238587	SCV000484687	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238587	SCV000503172	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 / Software predictions: Conflicting
Fundacion Hipercolesterolemia Familiar	RCV000238587	SCV000607467	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001385842	SCV001585835	pathogenic	Familial hypercholesterolemia	2023-09-15	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 172 of the LDLR protein (p.Asp172Asn). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10532689, 16806138). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp172 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10882754, 11194025, 20538126, 28028493), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects LDLR function (PMID: 25545329). 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. ClinVar contains an entry for this variant (Variation ID: 251266). This variant is also known as D151N.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000238587	SCV001653595	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced binding activity & LDL uptake versus WT
Ambry Genetics	RCV002338784	SCV002641057	likely pathogenic	Cardiovascular phenotype	2017-03-09	criteria provided, single submitter	clinical testing	The p.D172N variant (also known as c.514G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 514. The aspartic acid at codon 172 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple patients with familial hypercholesterolemia from different origins (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Chater R et al. Clin. Chim. Acta, 2006 Nov;373:62-9). This alteration was reported to segregate with the disease in the proband and three affected family members (Chater R et al. Clin. Chim. Acta, 2006 Nov;373:62-9). In vitro experiments suggested that this alteration resulted in deficient ligand binding while not affecting protein expression (Etxebarria A et al. Atherosclerosis, 2015 Feb;238:304-12). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000238587	SCV004237596	pathogenic	Hypercholesterolemia, familial, 1	2023-03-31	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238587	SCV000606142	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research