Submissions for variant NM_000527.5(LDLR):c.1502C>T (p.Ala501Val)

gnomAD frequency: 0.00001  dbSNP: rs755667663

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238372	SCV000295471	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238372	SCV000583839	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000519148	SCV000617511	likely pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.A480V; This variant is associated with the following publications: (PMID: 23375686, 25487149, 15823288, 26632531, 28932795, 25014035, 23833242, 16542394, 33794673, 32331935, 33418990, 34426522, 34037665, 34176852, 34074024, 31491741)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000770762	SCV000697199	likely pathogenic	Familial hypercholesterolemia	2019-02-28	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1502C>T (p.Ala501Val) results in a non-conservative amino acid change located in the LDLR class B repeat domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246260 control chromosomes, which does not exceed the estimated maximal expected allele frequency for a pathogenic LDLR variant of (0.0013). c.1502C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Damgaard 2005, Brusgaard 2006, Bertolini 2013, Mabuchi 2014), and was also found in a patient with early-onset myocardial infarction (Do 2015). This variant was identified in once in compound heterozygosity with another pathogenic variant in the LDLR gene (c.718G>A, p.Glu240Lys) in an adult male patient tested on the familal hypercholestolemia panel at our laboratory. No other clinically significant sequence variants were identified in the APOB, LDLR and PCSK9 genes, however no additional familial or clinical information was available. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and two laboratories classified the variant as likely pathogenic, while one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000770762	SCV001482453	likely pathogenic	Familial hypercholesterolemia		criteria provided, single submitter	research
Invitae	RCV000770762	SCV001574238	pathogenic	Familial hypercholesterolemia	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 501 of the LDLR protein (p.Ala501Val). This variant is present in population databases (rs755667663, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia or myocardial infarction (PMID: 15823288, 23375686, 25014035, 25487149, 28932795). This variant is also known as A480V. ClinVar contains an entry for this variant (Variation ID: 251874). 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. This variant disrupts the p.Ala501 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15256764, 16205024, 16806138, 23375686). 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.
Revvity Omics, Revvity	RCV000238372	SCV002022656	likely pathogenic	Hypercholesterolemia, familial, 1	2019-12-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000238372	SCV002516652	pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392745	SCV002699418	likely pathogenic	Cardiovascular phenotype	2021-04-08	criteria provided, single submitter	clinical testing	The p.A501V variant (also known as c.1502C>T), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1502. The alanine at codon 501 is replaced by valine, an amino acid with similar properties, and is located in the EGF precursor-like domain. This alteration, historically described as p.A480V, was detected along with a truncating LDLR alteration in a child with clinical homozygous familial hypercholesterolemia (FH) (Mabuchi H et al. Atherosclerosis, 2014 Sep;236:54-61). This variant has also been reported in multiple individuals with FH from a variety of ethnic backgrounds, as well as in myocardial infarction and coronary artery disease study cohorts; however, specific clinical details were limited (Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Meshkov A et al. Genes (Basel), 2021 Jan;12:[Epub ahead of print]). This allele was reported in two heterozygous individuals in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238372	SCV000606444	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000770762	SCV002086427	likely pathogenic	Familial hypercholesterolemia	2021-02-12	no assertion criteria provided	clinical testing