Submissions for variant NM_005629.4(SLC6A8):c.116G>A (p.Gly39Asp)

dbSNP: rs781997638

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000477133	SCV002600172	uncertain significance	Creatine transporter deficiency	2022-06-06	reviewed by expert panel	curation	The NM_005629.4(SLC6A8):c.116G>A (p.Gly39Asp) variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Aspartic Acid at amino acid 39 (p.Gly39Asp). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.107 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing (BP4). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:410221). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Invitae	RCV000477133	SCV000550818	uncertain significance	Creatine transporter deficiency	2022-08-09	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 39 of the SLC6A8 protein (p.Gly39Asp). This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. 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. 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 not expected to disrupt SLC6A8 protein function. ClinVar contains an entry for this variant (Variation ID: 410221).