Variant: NM_005629.4(SLC6A8):c.972_973CA[1] (p.Thr325fs)

CA16616640

410218 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: c8635a75-c6fd-4946-90e1-7fc444ee82c3

Approved on: 2024-05-02

Published on: 2024-06-12

HGVS expressions

NM_005629.4:c.972_973CA[1]
NM_005629.4(SLC6A8):c.972_973CA[1] (p.Thr325fs)
NC_000023.11:g.153693324_153693325del
CM000685.2:g.153693324_153693325del
NC_000023.10:g.152958779_152958780del
CM000685.1:g.152958779_152958780del
NC_000023.9:g.152611973_152611974del
NG_012016.1:g.10028_10029del
NG_012016.2:g.10028_10029del
ENST00000253122.10:c.974_975del
ENST00000253122.9:c.974_975del
ENST00000413787.1:c.123-3_123-2del
ENST00000430077.6:c.629_630del
ENST00000442457.1:c.58_59del
ENST00000467402.1:n.146-168_146-167del
ENST00000485324.1:n.1007_1008del
NM_001142805.1:c.974_975del
NM_001142806.1:c.629_630del
NM_005629.3:c.974_975del
NM_005629.4:c.974_975del
NM_001142805.2:c.974_975del

Pathogenic

• Met criteria codes: PVS1 PM2 PP4_Strong

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.972_973del (p.Thr325SerfsTer139) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two maternal half-brothers have been reported to be hemizygous for the variant, both with clinical features consistent with creatine transporter deficiency, markedly reduced creatine level on brain MRS, elevated urine creatine/creatinine ratio, and <3% transporter activity in fibroblasts (PMID 20602486) (PP4_Strong). This variant is not in gnomAD v2.1.1. or v4.1.0 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 410218). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on May 2, 2024)

Met criteria codes

• PVS1: The NM_005629.4:c.972_973del (p.Thr325SerfsTer139) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2: This variant is not in gnomAD v2.1.1. and v4.1.0 (PM2_Supporting).
• PP4_Strong: Two maternal half brothers have been reported to be hemizygous for the variant, both with clinical features consistent with creatine transporter deficiency, markedly reduced creatine on brain MRS, elevated urine creatine/creatinine ratio, and <3% transporter activity in fibroblasts (PMID 20602486) (PP4_Strong).