Submissions for variant NM_030777.4(SLC2A10):c.394C>T (p.Arg132Trp)

gnomAD frequency: 0.00010  dbSNP: rs121908173

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000616750	SCV000739644	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-12-22	criteria provided, single submitter	clinical testing	The p.R132W pathogenic mutation (also known as c.394C>T), located in coding exon 2 of the SLC2A10 gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported to co-occur in trans with other pathogenic variants in the SLC2A10 gene in probands with arterial tortuosity syndrome (Callewaert BL et al, Hum. Mutat. 2008 Jan; 29(1):150-8; Beyens A et al. Genet Med. 2018 Oct;20(10):1236-1245). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000004852	SCV000895251	uncertain significance	Arterial tortuosity syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000004852	SCV001468392	likely pathogenic	Arterial tortuosity syndrome	2021-03-30	criteria provided, single submitter	clinical testing	SLC2A10 NM_030777.3 exon 2 p.Arg132Trp (c.394C>T): This variant has been reported in the literature in the compound heterozygous state with another pathogenic variant, in at least 5 individuals with aterial tortuosity syndrome, segregating with disease in one affected family member (Callewaert 2008 PMID:17935213, Hardin 2018 PMID:28726533, Weerakkody 2018 PMID:29543232). This variant is present in 0.005% (7/129070) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/20-45354069-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:4590). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
GeneDx	RCV001558568	SCV001780546	likely pathogenic	not provided	2021-05-20	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# 4590; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29543232, 17935213, 28726533, 25392904)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004852	SCV001821368	pathogenic	Arterial tortuosity syndrome	2023-06-02	criteria provided, single submitter	clinical testing	Variant summary: SLC2A10 c.394C>T (p.Arg132Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251318 control chromosomes (gnomAD). c.394C>T has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Arterial Tortuosity Syndrome and has been found to segregate with the disease phenotype in at least one family (e.g. Beyens_2018, Callewaert_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29323665, 17935213). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=3) and VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV001558568	SCV002502030	likely pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing
Invitae	RCV000004852	SCV003788770	pathogenic	Arterial tortuosity syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 132 of the SLC2A10 protein (p.Arg132Trp). This variant is present in population databases (rs121908173, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive arterial tortuosity syndrome (PMID: 17935213, 28726533, 29543232). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4590). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC2A10 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004852	SCV004848860	likely pathogenic	Arterial tortuosity syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.Arg132Trp variant in SLC2A10 has been reported in the compound heterozygous state with another pathogenic variant in at least 5 individuals with features of arterial tortuosity syndrome and segregated with disease in one relative(Callewaert 2008 PMID:17935213, Hardin 2018 PMID:28726533, Weerakkody 2018 PMID:29543232, Beyens 2018 PMID: 29323665). It has also been reported in ClinVar (Variation ID:4590). This variant has been identified in 11/68012 of European alleles by gnomAD (https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive arterial tortuosity syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_VS.
CeGaT Center for Human Genetics Tuebingen	RCV001558568	SCV005041718	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	SLC2A10: PM3:Very Strong, PM2, PM5:Supporting
OMIM	RCV000004852	SCV000025028	pathogenic	Arterial tortuosity syndrome	2008-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000004852	SCV000195646	not provided	Arterial tortuosity syndrome		no assertion provided	literature only
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000616750	SCV000731235	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research