Submissions for variant NM_030777.4(SLC2A10):c.1276G>T (p.Gly426Trp)

gnomAD frequency: 0.00004  dbSNP: rs121908172

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199687	SCV000250723	likely pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 4589; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30090112, 17935213, 29907982)
Invitae	RCV000004851	SCV001386351	pathogenic	Arterial tortuosity syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 426 of the SLC2A10 protein (p.Gly426Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with arterial tortuosity syndrome and/or thoracic aortic aneurysm (PMID: 17935213, 29907982). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4589). 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 SLC2A10 protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV000004851	SCV002098364	likely pathogenic	Arterial tortuosity syndrome	2022-02-08	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,PP5
Ambry Genetics	RCV002371760	SCV002684915	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-12-06	criteria provided, single submitter	clinical testing	The p.G426W pathogenic mutation (also known as c.1276G>T), located in coding exon 2 of the SLC2A10 gene, results from a G to T substitution at nucleotide position 1276. The glycine at codon 426 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected in three probands with arterial tortuosity syndrome (ATS) who also had a second SLC2A10 variant in trans, one of which was a frameshift alteration (Callewaert BL et al. Hum. Mutat., 2008 Jan;29:150-8). This variant has also been detected in the homozygous state in a pediatric proband with features consistent with ATS (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000004851	SCV000025027	pathogenic	Arterial tortuosity syndrome	2008-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000004851	SCV000195653	not provided	Arterial tortuosity syndrome		no assertion provided	literature only