Submissions for variant NM_030777.4(SLC2A10):c.899T>G (p.Leu300Trp)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics Department, Hospital De La Santa Creu I Sant Pau	RCV003334359	SCV003923307	likely pathogenic	Arterial tortuosity syndrome	2023-04-14	criteria provided, single submitter	clinical testing	Identified in trans with an already known likely pathogenic variant (NM_030777.4:c.417T>A, ClinVar variation entry 161095). NM_030777.4:c.899T>G classified as likely pathogenic with ACMG/AMP evidences PM2-Moderate, PP3-Moderate, PM3-Moderate,PP4-Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701025	SCV005202608	likely pathogenic	Familial aortopathy	2024-07-11	criteria provided, single submitter	clinical testing	Variant summary: SLC2A10 c.899T>G (p.Leu300Trp) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251116 control chromosomes. c.899T>G has been reported in the literature as homozygous or compound heterozygous genotype in individuals affected with clinical features of Arterial Tortuosity Syndrome (Beyens_2018, Esmel-Vilomara_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29323665, 37619836). ClinVar contains an entry for this variant (Variation ID: 2501291). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003334359	SCV005834873	pathogenic	Arterial tortuosity syndrome	2024-03-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 300 of the SLC2A10 protein (p.Leu300Trp). This variant is present in population databases (rs771702107, gnomAD 0.009%). This missense change has been observed in individual(s) with arterial tortuosity syndrome (PMID: 29323665; Invitae). ClinVar contains an entry for this variant (Variation ID: 2501291). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC2A10 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.