ClinVar Genomic variation as it relates to human health

Identified in a patient with TAAD in published literature (PMID: 34498425); 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; This variant is associated with the following publications: (PMID: 30090112, 31589614, 19781076, 29323665, 34498425)

The SLC2A10 c.691C>T; p.Arg231Trp variant (rs146579504) has been described in the compound heterozygous state in individuals affected with arterial tortuosity syndrome (ATS) (Beyens 2018, Ritelli 2009). It is reported as pathogenic in ClinVar (Variation ID: 161106) and observed in the general population at a low overall frequency of 0.002% (6/276720 alleles) in the Genome Aggregation Database. The arginine at codon 231 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is damaging. Additionally, another variant at this position (c.692G>A; p.Arg231Gln) has been described in individuals with ATS and is considered pathogenic (Beyens 2018, Callewaert 2008). Based on available information, this variant is considered likely pathogenic. Pathogenic SLC2A10 variants are inherited in an autosomal recessive manner, and are associated with arterial tortuosity syndrome (ATS) (MIM: 208050) characterized by tortuosity and elongation of the large and medium-sized arteries, predisposition to aneurysms, vascular dissection, and pulmonary arteries stenosis as well as cutaneous, skeletal and other symptoms. This individual appears to be only a carrier of ATS. However, our analysis cannot detect variants in deep intronic or enhancer regions; therefore, the presence of additional pathogenic variants in these regions cannot be excluded. If an additional pathogenic variant, not detected by the current assay, is present on the opposite chromosome, this individual may be affected with ATS. References: Beyens A et al. Arterial tortuosity syndrome: 40 new families and literature review. Genet Med. 2018 Jan 11. Callewaert B et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008 Jan;29(1):150-8. Ritelli M et al. Arterial tortuosity syndrome in two Italian paediatric patients. Orphanet J Rare Dis. 2009 Sep 25;4:20.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 231 of the SLC2A10 protein (p.Arg231Trp). This variant is present in population databases (rs146579504, gnomAD 0.004%). This missense change has been observed in individual(s) with aortopathy and/or arterial tortuosity syndrome (PMID: 19781076, 34498425). 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: 161106). 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. This variant disrupts the p.Arg231 amino acid residue in SLC2A10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17935213, 23494979). 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.

The p.R231W variant (also known as c.691C>T), located in coding exon 2 of the SLC2A10 gene, results from a C to T substitution at nucleotide position 691. The arginine at codon 231 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in trans with a frameshift alteration in an individual with arterial tortuosity syndrome (Ritelli M et al. Orphanet J Rare Dis, 2009 Sep;4:20). Another alteration at the same codon, p.R231Q (c.692G>A), has been detected in trans with other pathogenic mutations in individuals with arterial tortuosity syndrome (Callewaert BL et al. Hum Mutat. 2008;29(1):150-158; Takahashi Y et al. Am J Med Genet A. 2013;161A(4):856-859). 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 majority of available evidence to date, this variant is likely to be pathogenic.

Variant interpretted as Likely pathogenic and reported on 05-29-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.