Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_001142805.2:c.338G>A

CA415077715

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: db7c163d-d7e1-4d7a-b958-45dd6a1748ea

Approved on: 2024-03-28

Published on: 2024-03-28

HGVS expressions

NM_001142805.2:c.338G>A

NC_000023.11:g.153690450G>A

CM000685.2:g.153690450G>A

NC_000023.10:g.152955905G>A

CM000685.1:g.152955905G>A

NC_000023.9:g.152609099G>A

NG_012016.1:g.7154G>A

NG_012016.2:g.7154G>A

ENST00000253122.10:c.338G>A

ENST00000675713.1:n.92G>A

ENST00000253122.9:c.338G>A

ENST00000430077.6:c.-8G>A

ENST00000476466.1:n.190G>A

NM_001142805.1:c.338G>A

NM_001142806.1:c.-8G>A

NM_005629.3:c.338G>A

NM_005629.4:c.338G>A

Uncertain Significance

PM2_Supporting PP3 PP4 PS3_Supporting

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.338G>A variant in SLC6A8 is a missense variant that is predicted to result in the substitution of glycine by aspartate at amino acid 113 (p.Gly113Asp). This variant has been previously reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in undetectable creatine transport activity, with 25uM creatine, when expressed in SLC6A8 deficient fibroblasts (PMID: 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024).

PM2_Supporting

The variant is absent in gnomAD v2.1.1. (PM2_Supporting)

PP3

The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). No impact on splicing predicted by SpliceAI.

PP4

This variant has been previously reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449).

PS3_Supporting

This variant was reported to result in undetectable creatine transport activity, with 25uM creatine, in SLC6A8 deficient fibroblasts (PMID: 23644449) (PS3_Supporting).

This variant was reported to result in undetectable creatine transport activity, with 25uM creatine, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine, in SLC6A8 deficient fibroblasts (see supplementary table; unpublished data from VUmc) (PMID: 23644449) (PS3_Supporting). PubMed:23644449

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