Submissions for variant NM_000527.5(LDLR):c.1223A>T (p.Glu408Val)

dbSNP: rs879254838

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237375	SCV002506337	likely pathogenic	Hypercholesterolemia, familial, 1	2021-12-16	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1223A>T (p.Glu408Val) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PP1_Moderate, PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis (data from 3 families: F1 - 2 affected family members have the variant, F2 - 2 affected family members have the variant, F3 - 1 affected family member has the variant) from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PP1_Moderate is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PS4_moderate - variant meets PM2 and was identified in 6 unrelated index cases, all fulfilling Simon-Broome criteria of definite FH, from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PS4_Moderate is met. PP3 - REVEL = 0.908. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 6 unrelated index cases (see details in PS4), so PP4 is met.
LDLR-LOVD, British Heart Foundation	RCV000237375	SCV000295311	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237375	SCV000540804	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV001235902	SCV001408611	pathogenic	Familial hypercholesterolemia	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 408 of the LDLR protein (p.Glu408Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 22698793). ClinVar contains an entry for this variant (Variation ID: 251740). 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. This variant disrupts the p.Glu408 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 14974088, 17347910, 19843101, 20236128). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237375	SCV001432553	pathogenic	Hypercholesterolemia, familial, 1	2019-01-26	criteria provided, single submitter	research
Ambry Genetics	RCV002365246	SCV002659638	likely pathogenic	Cardiovascular phenotype	2018-05-09	criteria provided, single submitter	clinical testing	The p.E408V variant (also known as c.1223A>T), located in coding exon 9 of the LDLR gene, results from an A to T substitution at nucleotide position 1223. The glutamic acid at codon 408 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in association with familial hypercholesterolemia (FH) (Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Dušková L et al. Atherosclerosis, 2011 May;216:139-45). In addition, alterations affecting the same amino acid, p.E408A and p.E408K, have also been reported in individuals with FH (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Hobbs HH et al. Hum. Mutat., 1992;1:445-66). This amino acid position is well 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.
GeneDx	RCV003114410	SCV003798849	likely pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Also known as p.(E387V); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as CHO cells transfected with this variant showed reduced plasma membrane expression and reduced LDL particle uptake (Duskova et al., 2020); This variant is associated with the following publications: (PMID: 21310417, 22698793, 32695144, 33740630)
Revvity Omics, Revvity	RCV000237375	SCV003829575	likely pathogenic	Hypercholesterolemia, familial, 1	2022-11-21	criteria provided, single submitter	clinical testing