ClinVar Miner

Submissions for variant NM_030777.4(SLC2A10):c.691C>T (p.Arg231Trp) (rs146579504)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000195605 SCV000884528 likely pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing 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.
GeneDx RCV000195605 SCV000250738 pathogenic not provided 2014-10-06 criteria provided, single submitter clinical testing p.Arg231Trp (CGG>TGG): c.691 C>T in exon 2 of the SLC2A10 gene (NM_030777.3). The R231W mutation in the SLC2A10 gene has been previously reported in association with ATS (Ritelli M et al., 2009). Ritelli et al. (2009) identified the mutation in conjunction with another SLCA10 mutation in one patient with healthy, non-consanguineous parents and unaffected siblings. The R231W mutation was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Located in the cytoplasmic loop between the sixth and seventh transmembrane domains of SLC2A10, R231W results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, a mutations in the same residue (R231Q) has been reported in association with ATS, further supporting the functional importance of this residue and region of the protein. In summary, R231W in the SLC2A10 gene is interpreted as a disease-causing mutation. This variant was found in TAAD
GeneReviews RCV000202453 SCV000195661 pathogenic Arterial tortuosity syndrome 2014-09-10 no assertion criteria provided literature only
Invitae RCV000202453 SCV000933700 uncertain significance Arterial tortuosity syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 231 of the SLC2A10 protein (p.Arg231Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs146579504, ExAC 0.006%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic in an individual affected with arterial tortuosity syndrome (PMID: 19781076). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 161106). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg231 amino acid residue in SLC2A10. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 17935213, 23494979), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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