Submissions for variant NM_005629.4(SLC6A8):c.626_627del (p.Pro209fs)

dbSNP: rs1603215223

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	RCV000786917	SCV002600181	likely pathogenic	Creatine transporter deficiency	2022-06-06	reviewed by expert panel	curation	The NM_005629.4:c.626_627del (p.Pro209ArgfsTer87) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was identified by clinical exome sequencing in one male proband with developmental delay and seizures, and his similarly affected brother. (PMID 32434645). While these clinical features are consistent with a diagnosis of creatine transporter deficiency, more data to support this diagnosis, such as elevated urine creatine and reduced creatine on brain magnetic resonance spectroscopy, are not available (PP4 is not met). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 635461). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV001585709	SCV001820160	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Identified in a male with cerebral creatine deficiency syndrome in published literature (Sun et al., 2020); Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32434645)
Invitae	RCV000786917	SCV002197826	pathogenic	Creatine transporter deficiency	2023-07-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 635461). This sequence change creates a premature translational stop signal (p.Pro209Argfs*87) in the SLC6A8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with creatine transporter deficiency (PMID: 32434645).
CeGaT Center for Human Genetics Tuebingen	RCV001585709	SCV002585147	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	SLC6A8: PVS1, PM2
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786917	SCV000925818	pathogenic	Creatine transporter deficiency	2018-12-12	no assertion criteria provided	clinical testing