Submissions for variant NM_000527.5(LDLR):c.788A>G (p.Asp263Gly)

gnomAD frequency: 0.00001  dbSNP: rs141681167

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233913	SCV001406528	pathogenic	Familial hypercholesterolemia	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 263 of the LDLR protein (p.Asp263Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 24507775, 28965616, 34297352; internal data). ClinVar contains an entry for this variant (Variation ID: 960398). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV001450038	SCV001653609	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411863	SCV002675592	likely pathogenic	Cardiovascular phenotype	2023-09-20	criteria provided, single submitter	clinical testing	The p.D263G variant (also known as c.788A>G), located in coding exon 5 of the LDLR gene, results from an A to G substitution at nucleotide position 788. The aspartic acid at codon 263 is replaced by glycine, an amino acid with similar properties. This variant has been identified in multiple individuals with familial hypercholesterolemia (FH) (Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 01;28:35-43; Ambry internal data). 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 6 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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.
Color Diagnostics, LLC DBA Color Health	RCV001233913	SCV004358494	likely pathogenic	Familial hypercholesterolemia	2023-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 263 in the LDLR type A repeat 6 of the LDLR protein. This variant is also known as p.Asp242Gly in the mature protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple heterozygous individuals affected with familial hypercholesterolemia (PMID: 24507775, 28958694, 28965616, 34297352; ClinVar SCV002675592.1, SCV001653609.1). This variant has also been observed in homozygous state in an individual affected with severe familial hypercholesterolemia, as well as in multiple heterozygous first-degree relatives affected with familial hypercholesterolemia (DOI:10.1016/j.atherosclerosis.2019.06.630). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV001450038	SCV004834025	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp242Gly in the mature protein) replaces aspartic acid with glycine at codon 263 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple heterozygous individuals affected with familial hypercholesterolemia (PMID: 24507775, 28958694, 28965616, 34297352; ClinVar SCV002675592.1). This variant has been observed in a homozygous individual affected with severe familial hypercholesterolemia, as well as in her multiple, heterozygous, first-degree relatives affected with familial hypercholesterolemia (Turner et al, 2019, https://doi.org/10.1016/j.atherosclerosis.2019.06.630). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001450038	SCV005045092	likely pathogenic	Hypercholesterolemia, familial, 1	2024-03-08	criteria provided, single submitter	clinical testing	The LDLR c.788A>G (p.Asp263Gly) variant has been reported in at least six unrelated individuals affected with familial hypercholesterolemia and is reported to segregate with disease in seven individuals in two families (Di Taranto MD et al., PMID: 34297352; Lange LA et al., PMID: 24507775; Pirillo A et al., PMID: 28965616; Scicali R et al., PMID: 28958694; Turner T et al., doi: https://doi.org/10.1016/j.atherosclerosis .2019.06.630). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by four submitters. Another variant in the same codon, c.787G>T (p.Asp263Tyr), has been reported as likely pathogenic (ClinVar Variation ID: 2719688). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to LDLR function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998753	SCV005625858	likely pathogenic	not provided	2024-07-23	criteria provided, single submitter	clinical testing	The LDLR c.788A>G (p.Asp263Gly) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 24507775 (2014), 28965616 (2017), 28958694 (2018), and 34297352 (2021)). The frequency of this variant in the general population, 0.0000066 (1/152204 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV004998753	SCV005879087	likely pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	The LDLR c.788A>G; p.Asp263Gly variant (rs141681167, ClinVar variation ID: 960398) is reported in the literature in heterozygous and homozygous individuals affected with familial hypercholesterolemia (Di Taranto 2021, Pirillo 2017, Scicali 2018). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.916). Based on available information, this variant is considered to be likely pathogenic. References: Di Taranto MD et al. Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement. Clin Genet. 2021 Nov;100(5):529-541. PMID: 34297352. Pirillo A et al. Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. Atheroscler Suppl. 2017 Oct;29:17-24. PMID: 28965616. Scicali R et al. Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical, genetic and atherosclerotic burden profile. Nutr Metab Cardiovasc Dis. 2018 Jan;28(1):35-43. PMID: 28958694.