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	2024-11-08	reviewed by expert panel	curation	The NM_005629.4:c.820G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 274 (p.Val274Met). This variant has been previously reported in one individual with hypotonia, global developmental delay, and microcephaly, but who was found to have normal urine creatine and guanidinoacetate levels on two separate occasions and a de novo variant in KAT6A as an alternate molecular cause of his symptoms (PMID 27133397) (BS2). In gnomAD v2.1.1, the highest population allele frequency is 0.00015 (14/91767 alleles) in the European (Non-Finnish) population and there are 4 hemizygotes across all populations, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.559, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 4416002). 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 Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458335	SCV000561166	benign	Creatine transporter deficiency	2024-07-09	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).