ClinVar Miner

Submissions for variant NM_030777.4(SLC2A10):c.515C>T (p.Thr172Ile) (rs143301610)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724210 SCV000227530 uncertain significance not provided 2014-10-07 criteria provided, single submitter clinical testing
GeneDx RCV000199609 SCV000250700 likely benign not specified 2017-09-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000199609 SCV000272444 uncertain significance not specified 2015-05-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr172Ile in SLC2A10 has not been previously reported in individuals with connective tissue d isorders, but has been identified in 0.1% (8/6610) of Finnish chromosomes and 0. 1% (81/66602) of European chromosomes by the Exome Aggregation Consortium (http: //; dbSNP rs143301610). Threonine (Thr) at position 172 i s not conserved in mammals or evolutionarily distant species and several birds, reptiles, and fish carry an isoleucine (Ile) at this position, supporting that t his change may be tolerated. In summary, while the clinical significance of the p.Thr172Ile variant is uncertain, these data suggest that it is more likely to b e benign.
Ambry Genetics RCV000252305 SCV000318891 benign Cardiovascular phenotype 2015-09-13 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Clinical Services Laboratory,Illumina RCV000319871 SCV000434153 uncertain significance Arterial tortuosity syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000319871 SCV000549181 uncertain significance Arterial tortuosity syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 172 of the SLC2A10 protein (p.Thr172Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs143301610, ExAC 0.1%). This variant has been reported in one individual with aortic dilation or dissection (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 195383). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000319871 SCV000743109 likely benign Arterial tortuosity syndrome 2017-01-27 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000319871 SCV000744122 likely benign Arterial tortuosity syndrome 2015-12-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000724210 SCV000884524 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770704 SCV000902181 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-08-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000199609 SCV001442581 likely benign not specified 2020-10-26 criteria provided, single submitter clinical testing Variant summary: SLC2A10 c.515C>T (p.Thr172Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 251304 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database (exomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in SLC2A10 causing Arterial Tortuosity Syndrome (0.0016). However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in North-western Europeans (allele frequency: 0.000173), suggesting that the variant could be a benign polymorphism. The variant, c.515C>T, has been reported in the literature in an individual with aortic dilation or dissection, however, further details were not provided on this case (Wooderchak-Donahue_2015). This report does not provide unequivocal conclusions about association of the variant with Arterial Tortuosity Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 5 calling it benign/likely benign, and 5 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000319871 SCV000745578 likely benign Arterial tortuosity syndrome 2017-07-17 no assertion criteria provided clinical testing

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