Submissions for variant NM_000527.5(LDLR):c.2026G>C (p.Gly676Arg)

dbSNP: rs745753810

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238171	SCV000295823	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518493	SCV003443108	likely pathogenic	Familial hypercholesterolemia	2023-09-21	criteria provided, single submitter	clinical testing	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.Gly676 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12417285, 31491741; Invitae). 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: 252176). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 26892515, 27932355, 30526649). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 676 of the LDLR protein (p.Gly676Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002518493	SCV005394294	pathogenic	Familial hypercholesterolemia	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2026G>C (p.Gly676Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250686 control chromosomes (gnomAD). c.2026G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Sharifi_2016, Li_2017, Cao_2018, Wang_2022, Xiao_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26892515, 27932355, 30526649, 36338372, 35727495, 35966514). ClinVar contains an entry for this variant (Variation ID: 252176). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000238171	SCV005417054	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5+PP3_Moderate+PS4_Supporting
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238171	SCV000606576	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research