Submissions for variant NM_000527.5(LDLR):c.1503G>A (p.Ala501=)

gnomAD frequency: 0.00008  dbSNP: rs368889457

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237830	SCV002817174	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-27	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1503G>A (p.Ala501=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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: PopMax MAF = 0.0002403 (0.02403%) in African/African American population exomes/genomes (gnomAD version). PP3: No REVEL score, splicing evaluation required. Functional data on splicing not available. B). Variant is exonic and at least 50bp upstream from canonical donor site and creates AG MES scores: de novo variant = 9.20; canonical acceptor = 6.76. Ratio de novo variant/canonical acceptor = 9.20/6.76 = 1.36 --- it is above 0.9 PP4: variant meets PM2, identified in 1 FH index case from PMID: 20145306 with WHO criteria, after alternative causes of high cholesterol were excluded.
LDLR-LOVD, British Heart Foundation	RCV000237830	SCV000295473	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237830	SCV000583840	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188900	SCV001356075	uncertain significance	Familial hypercholesterolemia	2023-04-27	criteria provided, single submitter	clinical testing	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction tools suggest that this variant may impact RNA splicing through creation of a novel acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 30293936). This variant has been identified in 11/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193180	SCV001361868	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1503G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251456 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1503G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Chmara 2010, Martin-Campos 2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 22881376, 30293936, 32719484). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6), likely benign (n=1), or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001188900	SCV001417719	uncertain significance	Familial hypercholesterolemia	2022-10-07	criteria provided, single submitter	clinical testing	This sequence change affects codon 501 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs368889457, gnomAD 0.03%). This variant has been observed in individual(s) with definite or suspected hypercholesterolemia (PMID: 20145306, 22881376). ClinVar contains an entry for this variant (Variation ID: 251876). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000237830	SCV001423092	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The c.1503G>A variant in LDLR has been reported in 4 individuals, including one Polish individual, with Familial Hypercholesterolemia (PMID: 20145306, Variation ID: 251876), and has been identified in 0.02403% (6/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368889457). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 251876). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple missense variants in the same region as c.1503G>A have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 251867, 251868, 251870, 265903, 251874, 251873, 251877). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_Supporting, PM1_Supporting (Richards 2015).
Ambry Genetics	RCV003298316	SCV004000122	uncertain significance	Cardiovascular phenotype	2023-03-19	criteria provided, single submitter	clinical testing	The c.1503G>A variant (also known as p.A501A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1503. This nucleotide substitution does not change the alanine at codon 501. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Chmara M et al. J Appl Genet, 2010;51:95-106; Martín-Campos JM et al. J Clin Lipidol, 2018 Sep;12:1452-1462). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV001193180	SCV001923080	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727654	SCV001975937	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001188900	SCV002086428	uncertain significance	Familial hypercholesterolemia	2020-02-19	no assertion criteria provided	clinical testing