Submissions for variant NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys)

gnomAD frequency: 0.00001  dbSNP: rs193922568

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237193	SCV000295406	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV001804888	SCV002051933	uncertain significance	Familial hypercholesterolemia	2021-03-15	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly440Cys in the mature protein) replaces glycine with cysteine at codon 461 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia from an Italian family (PMID: 16465405) and two Greek individuals affected with familial hypercholesterolemia (PMID: 23815734, 25463123, 27578104). This variant has been identified in 3/282248 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.
Invitae	RCV001804888	SCV003289210	likely pathogenic	Familial hypercholesterolemia	2023-09-08	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs193922568, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 461 of the LDLR protein (p.Gly461Cys). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 16465405, 23375686, 23815734, 35339733). This variant is also known as G440C. ClinVar contains an entry for this variant (Variation ID: 183113). 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. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). This variant disrupts the p.Gly461 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 35047021), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235078	SCV003934618	uncertain significance	not specified	2023-05-17	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1381G>T (p.Gly461Cys) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) 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 8e-06 in 250880 control chromosomes (gnomAD). c.1381G>T has been reported in the literature in several families with history of heart disease and hypercholesterolemia, however a limited number of members from each family were available for testing, making it difficult to confirm segregation (e.g. Cefalu_2006, Mollaki_2013). In vitro assaying the uptake of LDL in cells overexpressing the variant showed no damaging effect of this variant (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16465405, 23815734, 25647241). Three ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
All of Us Research Program, National Institutes of Health	RCV000237193	SCV004820307	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly440Cys in the mature protein) replaces glycine with cysteine at codon 461 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia from an Italian family (PMID: 16465405) and two Greek individuals affected with familial hypercholesterolemia (PMID: 23815734, 25463123, 27578104). This variant has been identified in 3/282248 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161985	SCV000189560	not provided	not provided		no assertion provided	in vitro