Submissions for variant NM_005629.4(SLC6A8):c.820G>A (p.Val274Met)

gnomAD frequency: 0.00005  dbSNP: rs782208622

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000458335	SCV002600184	uncertain significance	Creatine transporter deficiency	2022-06-06	reviewed by expert panel	curation	The NM_005629.4:c.820G>A variant in SLC6A8 is a missense substitution predicted to cause substitution of valine by methionine at amino acid 274 (p.Val274Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001526 in the European non-Finnish population, lower than the ClinGen CCDS VCEP threshold for BS1 (>0.0002), and higher than the threshold for PM2_Supporting (<0.00002), and therefore not meeting any allele frequency criteria. There are 4 hemizygotes in gnomAD v2.1.1. In addition, a male proband with hypotonia, global developmental delay, and microcephaly has been reported to have the variant, but was found to have normal urine creatine and guanidinoacetate levels on two separate occasions, and a de novo variant in KAT6A, which was asserted to be a possible cause of his clinical symptoms (PMID 27133397) (BS2). The computational predictor REVEL gives a score of 0.559 which is neither predicts a damaging nor benign impact on SLC6A8 function. There is a ClinVar entry for this variant (Variation ID: 416002. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458335	SCV000561166	benign	Creatine transporter deficiency	2024-01-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001528827	SCV001823970	likely benign	not provided	2018-07-27	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528827	SCV001741233	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528827	SCV001970261	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003899988	SCV004715504	likely benign	SLC6A8-related disorder	2022-04-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).