Submissions for variant NM_000527.5(LDLR):c.1196C>A (p.Ala399Asp)

dbSNP: rs875989918

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211653	SCV000295289	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249013	SCV001422863	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Ala399Asp variant in LDLR has been reported in 3 individuals with familial hypercholesterolemia (PMID: 22883975, 9259195, 11810272), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 226350). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249013	SCV002277740	pathogenic	Familial hypercholesterolemia	2023-08-10	criteria provided, single submitter	clinical testing	This variant disrupts the p.Ala399 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10634824, 15241806, 16250003, 16343504, 21925044, 23375686, 26723464). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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: 226350). This variant is also known as A378D. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 11810272, 21382890, 22883975; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 399 of the LDLR protein (p.Ala399Asp).
Ambry Genetics	RCV002336590	SCV002644422	pathogenic	Cardiovascular phenotype	2018-10-23	criteria provided, single submitter	clinical testing	The p.A399D pathogenic mutation (also known as c.1196C>A), located in coding exon 9 of the LDLR gene, results from a C to A substitution at nucleotide position 1196. The alanine at codon 399 is replaced by aspartic acid, an amino acid with dissimilar properties, and is located in the EGF precursor-like domain. This variant (also described as p.A378D) has been reported in multiple individuals from a variety of ethnic backgrounds with familial hypercholesterolemia (FH) (Day IN et al. Hum. Mutat., 1997;10:116-27; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). In addition, an alternate amino acid substitution at this position, p.A399T (also known as p.A378T or FH-Nuoro), has also been reported in individuals with FH (Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211653	SCV000268603	pathogenic	Hypercholesterolemia, familial, 1	2010-03-26	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211653	SCV000606353	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research