Submissions for variant NM_000527.5(LDLR):c.797A>G (p.Asp266Gly)

dbSNP: rs879254678

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237457	SCV002568112	likely pathogenic	Hypercholesterolemia, familial, 1	2021-11-14	reviewed by expert panel	curation	The NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.796A>T (p.Asp266Tyr) (ClinVar ID 251456) – Pathogenic by these guidelines, - NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 3 variants in the same codon classified as Pathogenic by these guidelines; PM2 - This variant is absent from gnomAD (gnomAD v2.1.1); PP3 - REVEL = 0.98; PP4 - Identified in 2 unrelated index cases fulfilling Simon-Broome criteria (published in PMID: 32331935); PS4_Supporting - Variant meets PM2. Identified in 2 unrelated index cases fulfilling Simon-Broome criteria (published in PMID: 32331935);
LDLR-LOVD, British Heart Foundation	RCV000237457	SCV000294977	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229239	SCV001401679	likely pathogenic	Familial hypercholesterolemia	2022-11-29	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 12417285, 15256764, 28932795, 32331935). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11196104, 20663204, 21310417, 22698793, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 251457). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 266 of the LDLR protein (p.Asp266Gly).
Ambry Genetics	RCV002418053	SCV002681635	likely pathogenic	Cardiovascular phenotype	2022-04-11	criteria provided, single submitter	clinical testing	The p.D266G variant (also known as c.797A>G), located in coding exon 5 of the LDLR gene, results from an A to G substitution at nucleotide position 797. The aspartic acid at codon 266 is replaced by glycine, an amino acid with similar properties. This alteration, which is also known as p.D245G, has been reported in individuals with familial hypercholesterolemia (FH) (Hobbs HH et al. Hum Mutat, 1992;1:445-66; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Tada H et al. Pract Lab Med, 2015 Apr;1:22-27). This alteration impacts 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). Based on internal structural analysis, this alteration has a deleterious impact. 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.