Submissions for variant NM_030777.4(SLC2A10):c.395G>A (p.Arg132Gln)

gnomAD frequency: 0.00005  dbSNP: rs376346077

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001837619	SCV002098150	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30090112)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002542811	SCV003478869	pathogenic	Arterial tortuosity syndrome	2024-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 132 of the SLC2A10 protein (p.Arg132Gln). This variant is present in population databases (rs376346077, gnomAD 0.01%). This missense change has been observed in individual(s) with arterial tortuosity syndrome (PMID: 29323665). ClinVar contains an entry for this variant (Variation ID: 1342029). 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%. This variant disrupts the p.Arg132 amino acid residue in SLC2A10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17935213, 28726533, 29543232). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331215	SCV004037724	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: SLC2A10 c.395G>A (p.Arg132Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251334 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC2A10 causing Aortopathy (6e-05 vs 0.0016), allowing no conclusion about variant significance. c.395G>A has been reported in the literature in individuals affected with arterial tortuosity syndrome (Beyens_2018). These data indicate that the variant may 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, 30090112). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.