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

gnomAD frequency: 0.00100  dbSNP: rs143301610

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724210	SCV000227530	uncertain significance	not provided	2014-10-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000724210	SCV000250700	uncertain significance	not provided	2021-06-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25944730)
Laboratory for Molecular Medicine, Mass General Brigham 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: //exac.broadinstitute.org; 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	RCV000770704	SCV000318891	benign	Familial thoracic aortic aneurysm and aortic dissection	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 Laboratory Services, 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	likely benign	Arterial tortuosity syndrome	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000319871	SCV000884524	uncertain significance	Arterial tortuosity syndrome	2022-04-06	criteria provided, single submitter	clinical testing	The SLC2A10 c.515C>T; p.Thr172Ile variant (rs143301610) is reported in the literature in an individual affected with aortopathy/aortic dilation (Wooderchak-Donahue 2015), but its clinical significance was not determined. This variant is also reported in ClinVar (Variation ID: 195383) and is found in the non-Finnish European population with an allele frequency of 0.135% (174/129040 alleles) in the Genome Aggregation Database. The threonine at codon 172 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.148). Due to limited information, the clinical significance of the p.Thr172Ile variant is uncertain at this time. References: Wooderchak-Donahue W et al., Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. 2015 Aug;167A(8):1747-57. PMID: 25944730.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770704	SCV000902181	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000199609	SCV001442581	likely benign	not specified	2022-02-25	criteria provided, single submitter	clinical testing	Variant summary: SLC2A10 c.515C>T (p.Thr172Ile) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014and classified the variant likely benign (n=2) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000319871	SCV003920483	likely benign	Arterial tortuosity syndrome	2022-10-26	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in one individual with aortic dilation/dissection (Wooderchak-Donahue 2015 PMID:25944730). However, this variant is also present in 0.1% (174/129040) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-45354190-C-T) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:195383). This variant amino acid Isoleucine (Ile) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000724210	SCV004154645	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SLC2A10: BP4