Variant: NM_001142805.2:c.1637G>A

CA415090808

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 4f74113e-6b39-4480-8675-0fcdb4a76703

Approved on: 2023-12-14

Published on: 2023-12-14

HGVS expressions

NM_001142805.2:c.1637G>A
NC_000023.11:g.153694789G>A
CM000685.2:g.153694789G>A
NC_000023.10:g.152960244G>A
CM000685.1:g.152960244G>A
NC_000023.9:g.152613438G>A
NG_012016.1:g.11493G>A
NG_012016.2:g.11493G>A
ENST00000253122.10:c.1667G>A
ENST00000253122.9:c.1667G>A
ENST00000430077.6:c.1322G>A
ENST00000485324.1:n.1974G>A
NM_001142805.1:c.1637G>A
NM_001142806.1:c.1322G>A
NM_005629.3:c.1667G>A
NM_005629.4:c.1667G>A

Pathogenic

• Met criteria codes: PM2_Supporting PP4 PVS1

• Not Met criteria codes: PS4

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.1667G>A (p.Trp556Ter) variant in SLC6A8 is is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 12/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Although the variant is in the penultimate exon of the gene, it is upstream of last 50bp. Therefore, nonsense-mediated decay is not predicted to occur (PVS1). This variant has been reported in two male probands, from different countries, with the diagnosis of creatine transporter deficiency (PMID: 22281021, 34050321). For one of these individuals, the diagnosis was confirmed by elevated creatine to creatinine ratio in urine and the variant was identified by exome sequencing (PMID: 34050321) (PP4). Therefore is insufficient evidence to apply PS4 for the second individual. The variant is absent in gnomAD v4.0. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on December 14, 2023)

Met criteria codes

• PM2_Supporting: The variant is absent in gnomAD v4.0. (PM2_Supporting).
• PP4: The variant has been reported in a male with biochemical confirmation of elevated creatine to creatinine ratio in urine ( PMID: 34050321) (PP4).
• PVS1: The NM_005629.4:c.1667G>A (p.Trp556Ter) variant in SLC6A8 is is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 12/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). [in penultimate exon but upstream of last 50bp, so NMD predicted]

Not Met criteria codes

• PS4: This variant has been reported in one male proband reported to have creatine transporter deficiency, but no additional clinical/biochemical data was provided; thus PS4 is not met (PMID: 22281021).