Submissions for variant NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)

dbSNP: rs879254459

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237444	SCV004022465	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP1, PP3, PP4, PS4_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: This variant is absent from gnomAD (gnomAD v2.1.1) - PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID: 25936346. - PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID: 25936346 - PP3: REVEL = 0.93 - PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID: 25936346)
LDLR-LOVD, British Heart Foundation	RCV000237444	SCV000294587	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	RCV000237444	SCV000503126	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 with co-segregation / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237444	SCV000583648	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814794	SCV000955220	uncertain significance	Familial hypercholesterolemia	2018-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 100 of the LDLR protein (p.Asp100Asn). 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 affected with familial hypercholesterolemia (PMID: 15199436, 25936346). This variant is also known as D79N in the literature. ClinVar contains an entry for this variant (Variation ID: 251121). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002436073	SCV002751463	likely pathogenic	Cardiovascular phenotype	2021-12-23	criteria provided, single submitter	clinical testing	The p.D100N variant (also known as c.298G>A and legacy p.D79N), located in coding exon 3 of the LDLR gene, results from a G to A substitution at nucleotide position 298. The aspartic acid at codon 100 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypercholesterolemia, including at least two homozygous cases (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Li H et al. Gene, 2015 Sep;569:313-7; Hu M et al. J. Atheroscler. Thromb., 2016 May;23:520-31; Moss S et al. Cardiovasc Revasc Med, 2018 12;19:20-22; Hsiung YC et al. Atherosclerosis, 2018 10;277:440-447). Based on internal structural analysis, this variant is deleterious, impacting a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 2 (Ambry internal data; Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.