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.1151C>A

CA415086302

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: a54c42ed-c369-4de3-979b-8c1c5900034e

Approved on: 2024-05-19

Published on: 2024-05-23

HGVS expressions

NM_001142805.2:c.1151C>A

NC_000023.11:g.153693944C>A

CM000685.2:g.153693944C>A

NC_000023.10:g.152959399C>A

CM000685.1:g.152959399C>A

NC_000023.9:g.152612593C>A

NG_012016.1:g.10648C>A

NG_012016.2:g.10648C>A

ENST00000253122.10:c.1181C>A

ENST00000253122.9:c.1181C>A

ENST00000413787.1:c.258-260C>A

ENST00000430077.6:c.836C>A

ENST00000442457.1:c.235C>A

ENST00000457723.1:c.165C>A

ENST00000467402.1:n.280C>A

ENST00000485324.1:n.1214C>A

NM_001142805.1:c.1151C>A

NM_001142806.1:c.836C>A

NM_005629.3:c.1181C>A

NM_005629.4:c.1181C>A

Uncertain Significance

PM2_Supporting PP4_Strong

PP3 PP1 BP4

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.1181C>A variant in SLC6A8 is predicted to result in a missense substitution of threonine by lysine at amino acid 394 (p.Thr394Lys). A 5 year old Chinese male, hemizygous for the variant, has been reported with clinical features consistent with creatine tranporter deficiency, elevated creatine/creatinine ratio in urine (value not provided), and decreased creatine peak on brain MRS (PP4_Strong). A brother with similar clinical features, but no biochemical or MRS test results available, is also hemizygous for the variant, while the heterozygous mother is “physically normal” with normal creatine on MRS (insufficient evidence to apply PP1 based on the specifications of the ClinGen CCDS VCEP). The variant is absent in gnomAD v4.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.653 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI predicts that the variant has no impact on splicing. In summary, this variant is of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on May 19, 2024)

PM2_Supporting

The variant is absent in gnomAD v4.0. (PM2_Supporting).

PP4_Strong

A 5 year old Chinese male has been reported with clinical features consistent with creatine tranporter deficiency, elevated creatine/creatinine ratio in urine and decreased creatine peak who is hemizygous for the variant, which was identified by targeted exome sequencing (PP4_Strong).

PP3

The computational predictor REVEL gives a score of 0.653 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function.

PP1

Affected male with a brother with similar clinical features (but no biochemical or MRS data for the brother) is also hemizygous for the variant. The mother is heterozygous and “physically normal” with normal creatine on MRS and normal brain MRI. (insufficient data to apply PP1).

BP4

The computational predictor REVEL gives a score of 0.653 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function.

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