Variant: NM_005629.4(SLC6A8):c.1428C>G (p.Tyr476Ter)

CA415087494

1802549 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance (dominant (HP:0001423))

UUID: 20afb38a-1bd4-48b1-a126-8ea9ccdadf36

Approved on: 2024-02-22

Published on: 2024-03-29

HGVS expressions

NM_005629.4:c.1428C>G
NM_005629.4(SLC6A8):c.1428C>G (p.Tyr476Ter)
NC_000023.11:g.153694379C>G
CM000685.2:g.153694379C>G
NC_000023.10:g.152959834C>G
CM000685.1:g.152959834C>G
NC_000023.9:g.152613028C>G
NG_012016.1:g.11083C>G
NG_012016.2:g.11083C>G
ENST00000253122.10:c.1428C>G
ENST00000253122.9:c.1428C>G
ENST00000413787.1:c.357C>G
ENST00000430077.6:c.1083C>G
ENST00000442457.1:c.482C>G
ENST00000485324.1:n.1649C>G
NM_001142805.1:c.1398C>G
NM_001142806.1:c.1083C>G
NM_005629.3:c.1428C>G
NM_001142805.2:c.1398C>G

Pathogenic

• Met criteria codes: PP4 PVS1 PM2_Supporting

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.1428C>G (p.Tyr476Ter) variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 10/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported a male with intellectual disability, autistic features, seizures and absent creatine peak on brain MRS (PMID: 29435807) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1802549). In summary, this variant meets the 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 Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on February 22, 2024).

Met criteria codes

• PP4: At least one male patient with this variant had absent creatine ascertained by brain magnetic resonance spectroscopy; urine creatine/creatinine ratio was not performed (PMID: 29435807).
• PVS1: The NM_005629.4: c.1428C>G variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 10 of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: The variant is absent in gnomAD v2.1.1.