Submissions for variant NM_005629.4(SLC6A8):c.76G>A (p.Gly26Arg)

gnomAD frequency: 0.00002  dbSNP: rs1233444890

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000796965	SCV002600197	uncertain significance	Creatine transporter deficiency	2022-06-06	reviewed by expert panel	curation	The NM_005629.4(SLC6A8):c.76G>A (p.Gly26Arg) variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Arginine at amino acid 26 (p.Gly26Arg). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000257 (2/77768 alleles) in the European population, and there is 1 hemizygote present in this population database, therefore PM2_Supporting criteria is not met. The computational predictor REVEL gives a score of 0.079 which is below the threshold of 0.25, evidence and does not predict a damaging effect on SLC6A8 function. While functional studies were completed for the SLC6A8 c.76G>A (p.Gly26Arg) (PMID:17465020), they did not meet the specifications required for functional studies by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (<125uM Creatine used for transport assays). This variant has been reported in an individual in the literature (PMID:16738945), however biochemical evidence of Creatine Transport Deficiency (elevated urine creatine:creatinine) was not obtained for this individual, therefore it does not meet criteria established for PP4. There is a ClinVar entry for this variant (Variation ID:655315). 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): BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Invitae	RCV000796965	SCV000936501	likely benign	Creatine transporter deficiency	2024-01-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816854	SCV002066229	uncertain significance	not specified	2021-01-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SLC6A8 gene demonstrated a sequence change, c.76G>A, in exon 1 that results in an amino acid change, p.Gly26Arg. This sequence change has been described in the gnomAD database in two individuals with an overall population frequency of 0.003% (dbSNP NA). The p.Gly26Arg change has been described in one individual with intellectual disability (PMID: 16738945). Functional studies did not demonstrate a significant impact on SLC6A8 protein function in the presence of this sequence change (PMID: 17465020). The p.Gly26Arg change affects a poorly conserved amino acid residue located in a domain of the SLC6A8 protein that is not known to be functional. The p.Gly26Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly26Arg change remains unknown at this time.
GeneDx	RCV001824372	SCV002074077	likely benign	not provided	2021-05-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17465020, 23408511, 16738945)
Natera, Inc.	RCV001830713	SCV002084546	likely benign	Creatine deficiency syndrome 1	2020-05-07	no assertion criteria provided	clinical testing