Submissions for variant NM_000527.5(LDLR):c.1004G>T (p.Gly335Val)

dbSNP: rs869320650

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238578	SCV004022377	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1004G>T (p.Gly335Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.874. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria of definite FH from PMID: 10735632 (Lombardi MP et al. 2000). so PP4 is met.
LDLR-LOVD, British Heart Foundation	RCV000238578	SCV000295130	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Fundacion Hipercolesterolemia Familiar	RCV000238578	SCV000607542	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Ambry Genetics	RCV002401931	SCV002710223	likely pathogenic	Cardiovascular phenotype	2017-09-14	criteria provided, single submitter	clinical testing	The p.G335V variant (also known as c.1004G>T), located in coding exon 7 of the LDLR gene, results from a G to T substitution at nucleotide position 1004. The glycine at codon 335 is replaced by valine, an amino acid with dissimilar properties. This alteration, also known as G314V, has been reported in familial hypercholesterolemia (FH) cohorts in the Netherlands and Spain (Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration affecting the same amino acid, G335S, has been described in a number of FH cohorts (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Rabacchi C et al. J Clin Lipidol Apr;10:944-952.e1; Bañares VG et al. J Clin Lipidol Feb;11:524-531). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519844	SCV003443159	likely pathogenic	Familial hypercholesterolemia	2022-09-21	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 sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 335 of the LDLR protein (p.Gly335Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10735632). This variant is also known as G314V. ClinVar contains an entry for this variant (Variation ID: 251587). 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.Gly335 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28502510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238578	SCV000606292	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research