Variant: NM_005629.4(SLC6A8):c.342G>C (p.Gln114His)

CA415077745

940774 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: d23454a7-c8b9-4e46-badd-c58073e5dc7a

Approved on: 2024-05-02

Published on: 2024-06-12

HGVS expressions

NM_005629.4:c.342G>C
NM_005629.4(SLC6A8):c.342G>C (p.Gln114His)
NC_000023.11:g.153690454G>C
CM000685.2:g.153690454G>C
NC_000023.10:g.152955909G>C
CM000685.1:g.152955909G>C
NC_000023.9:g.152609103G>C
NG_012016.1:g.7158G>C
NG_012016.2:g.7158G>C
ENST00000253122.10:c.342G>C
ENST00000675713.1:n.96G>C
ENST00000253122.9:c.342G>C
ENST00000430077.6:c.-4G>C
ENST00000476466.1:n.194G>C
NM_001142805.1:c.342G>C
NM_001142806.1:c.-4G>C
NM_005629.3:c.342G>C
NM_001142805.2:c.342G>C

Likely Pathogenic

• Met criteria codes: PM6_Supporting PP4_Strong PP3 PM2_Supporting

• Not Met criteria codes: PM5

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.342G>C variant in SLC6A8 is predicted to result in the substitution of glutamine by histidine at amino acid 114 (p.Gln114His). The variant has been reported in a male with clinical features consistent with creatine transporter deficiency, markedly elevated urine creatine, and markedly reduced creatine on brain MRS (Association for Creatine Deficiencies registry - CreatineINFO) (PP4_Strong). His mother does not carry the variant; maternity was not confirmed (PM6). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.859 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). Another amino acid change at the same position, c.340C>A (p.Gln114Lys) (ClinVar Variation ID: 561109) has been classified as a VUS by the ClinGen CCDS VCEP. There is a ClinVar entry for this variant (Variation ID: 940774). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine deficiency syndrome. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM6, PP3, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 2, 2024)

Met criteria codes

• PM6_Supporting: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4_Strong: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: The computational predictor REVEL gives a score of 0.859 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). SpliceAI predicts no impact on splicing.
• PM2_Supporting: The variant is absent in gnomAD v2.1.1. (PM2_Supporting).

Not Met criteria codes

• PM5: Another amino acid change at the same position, c.340C>A (p.Gln114Lys) (ClinVar Variation ID: 561109) has been classified as a VUS by the ClinGen CCDS VCEP.