Submissions for variant NM_005629.4(SLC6A8):c.92C>T (p.Pro31Leu)

gnomAD frequency: 0.00011  dbSNP: rs868950793

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	RCV000694042	SCV002600171	uncertain significance	Creatine transporter deficiency	2022-06-06	reviewed by expert panel	curation	The NM_005629.4(SLC6A8):c.92C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 31 (p.Pro31Leu). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0001300 (4/30763 alleles) in the European population with 1 hemizygote, which is >0.0002 and >1 hemizygote, therefore PM2_Supporting criteria is not applicable. The computational predictor REVEL gives a score of 0.114 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. This variant has been reported in a single individual in the literature (PMID:31222513) in a proband (case 1) with seizures, neurological regression, and spasticity who was found by WES to be hemizygous for the c.92C>T (p.Pro31Leu) variant, however biochemical studies were not performed to confirm creatine transporter deficiency, therefore this proband cannot be used as evidence for SLC6A8 variant classification. There is a ClinVar entry for this variant (Variation ID:572616). 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	RCV000694042	SCV000822468	benign	Creatine transporter deficiency	2024-01-29	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000694042	SCV000891652	uncertain significance	Creatine transporter deficiency	2017-12-30	criteria provided, single submitter	curation
GeneDx	RCV000842126	SCV000984122	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31222513)
CeGaT Center for Human Genetics Tuebingen	RCV000842126	SCV001150478	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000694042	SCV003823850	uncertain significance	Creatine transporter deficiency	2023-05-23	criteria provided, single submitter	clinical testing