ClinVar Miner

Submissions for variant NM_030777.4(SLC2A10):c.1330C>T (p.Arg444Ter)

gnomAD frequency: 0.00002  dbSNP: rs370547023
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492992 SCV000583136 likely pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing The R444X variant in the SLC2A10 gene has been reported in an Italian patient who was compound heterozygous for theR444X nonsense variant and the E437K missense variant (Drera et al., 2007). Drera et al. (2007) describe a 14 year old child with clinical features of ATS including stenosis, and tortuosity of the left pulmonary artery, tortuosity of carotid, vertebral, and intracerebral arteries and a family history significant for two deceased siblings with findings suggestive of ATS. R444X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Nemeth et al. (2016) performed in vivo studies from fibroblasts of the patient described by Drera et al. (2007) demonstrating the absence of mRNA due to nuclear mediated decay, with restoration of normal endomembrane transport of DAA when transfected with wild-type SCL10A2. Other nonsense variants in the SLC2A10 gene have been reported in Human Gene Mutation Database in association with ATS (Stenson et al., 2014). Furthermore, the R444X variant is not observed at asignificant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). In summary, although R444X in the SLC2A10 gene is interpreted as a likely pathogenic variant
Invitae RCV000202558 SCV001234205 pathogenic Arterial tortuosity syndrome 2022-08-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 161101). This premature translational stop signal has been observed in individual(s) with arterial tortuosity syndrome (PMID: 17163528). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs370547023, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg444*) in the SLC2A10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A10 are known to be pathogenic (PMID: 17935213, 22488877, 23494979).
Revvity Omics, Revvity Omics RCV000202558 SCV002020701 pathogenic Arterial tortuosity syndrome 2020-06-12 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV000202558 SCV002098370 pathogenic Arterial tortuosity syndrome 2022-02-08 criteria provided, single submitter clinical testing ACMG categories: PVS1,PP3,PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202558 SCV003801206 likely pathogenic Arterial tortuosity syndrome 2023-01-05 criteria provided, single submitter clinical testing Variant summary: SLC2A10 c.1330C>T (p.Arg444X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position have been reported in association with Arterial tortuosity syndrome in HGMD. The variant allele was found at a frequency of 4e-06 in 251470 control chromosomes. c.1330C>T has been reported in the literature in an individual affected with Arterial Tortuosity Syndrome (Drera_2007). Experimental evidence from fibroblasts from the patient reported in Drera, et al showed the genotype resulted in markedly reduced transport of DAA through endomembranes (Nemeth_2016) as well as absence of the typical patterns of GLUT10 perinuclear and mitochondrial decoration via immunostaining (Gamberucci_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV003380494 SCV004098628 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-07-31 criteria provided, single submitter clinical testing The p.R444* pathogenic mutation (also known as c.1330C>T), located in coding exon 3 of the SLC2A10 gene, results from a C to T substitution at nucleotide position 1330. This changes the amino acid from an arginine to a stop codon within coding exon 3. This variant was has been detected in the compound heterozygous state with a second SLC2A10 alteration in an individual with arterial tortuosity syndrome (Drera B et al. Am J Med Genet A, 2007 Jan;143A:216-8). Functional studies have indicated this variant impacts protein function (Zoppi N et al. Hum Mol Genet, 2015 Dec;24:6769-87; Németh CE et al. FEBS Lett, 2016 Jun;590:1630-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneReviews RCV000202558 SCV000195655 not provided Arterial tortuosity syndrome no assertion provided literature only

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