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.301G>A

CA415077486

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: fcc6a61c-4131-4c16-935d-894f4e5a3e05

Approved on: 2024-03-25

Published on: 2024-03-25

HGVS expressions

NM_001142805.2:c.301G>A

NC_000023.11:g.153690413G>A

CM000685.2:g.153690413G>A

NC_000023.10:g.152955868G>A

CM000685.1:g.152955868G>A

NC_000023.9:g.152609062G>A

NG_012016.1:g.7117G>A

NG_012016.2:g.7117G>A

ENST00000253122.10:c.301G>A

ENST00000675713.1:n.55G>A

ENST00000253122.9:c.301G>A

ENST00000430077.6:c.-45G>A

ENST00000476466.1:n.153G>A

NM_001142805.1:c.301G>A

NM_001142806.1:c.-45G>A

NM_005629.3:c.301G>A

NM_005629.4:c.301G>A

Uncertain Significance

PM2

BP4 PP1 PP4 PP3

Evidence Links 0

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.301G>A variant in SLC6A8 is predicted to results in the substitution of glycine by arginine at amino acid 101 (p.Gly101Arg). The variant has been reported in two brothers from China and their mother. The proband has developmental delays and seizures, normal guanidinoacetate and mildly reduced creatine in blood. Urine creatine level, brain creaine level on MRS, and creatine uptake studies are not available. Insufficient evidence to apply PP4 or PP1) (PMID: 35588794). The variant is absent in gnomAD v2.1.1. and v4.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.685 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI gave a score for acceptor gain of 0.34, 25 bp upstream, but the impact on splicing is unclear. In summary, the variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0.): PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on March 18, 2024)

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

The computational predictor REVEL gives a score of 0.685 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function.

PP1

The mother is heterozygous, and 12 year-old brother, with developmental delay, is hemizygous for the variant. No further details. Insufficient to apply PP1 (PMID: 35588794)

PP4

The variant has been reported in two brothers from China and their mother. The proband has developmental delays and seizures, normal guanidinoacetate and mildly reduced creatine in blood. Urine creatine level, brain creaine level on MRS, and creatine uptake studies are not available. In sufficient evidence to apply PP4 (PMID: 35588794).

PP3

The computational predictor REVEL gives a score of 0.685 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI, acceptor gain (0.34, 25 bp).

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