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.1362+24_1363-30del

CA2695237935

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 859fd587-83d6-4e9d-bb32-f46e1baf4756

Approved on: 2024-04-25

Published on: 2024-06-24

HGVS expressions

NM_001142805.2:c.1362+24_1363-30del

NC_000023.11:g.153694291_153694314del

CM000685.2:g.153694291_153694314del

NC_000023.10:g.152959746_152959769del

CM000685.1:g.152959746_152959769del

NC_000023.9:g.152612940_152612963del

NG_012016.1:g.10995_11018del

NG_012016.2:g.10995_11018del

ENST00000253122.10:c.1392+24_1393-30del

ENST00000253122.9:c.1392+24_1393-30del

ENST00000413787.1:c.321+24_322-30del

ENST00000430077.6:c.1047+24_1048-30del

ENST00000442457.1:c.446+24_447-30del

ENST00000485324.1:n.1561_1584del

NM_001142805.1:c.1362+24_1363-30del

NM_001142806.1:c.1047+24_1048-30del

NM_005629.3:c.1392+24_1393-30del

NM_005629.4:c.1392+24_1393-30del

Pathogenic

PP4_Strong PVS1_Moderate PS4_Supporting PM2_Supporting PM6

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.1392+24_1393-30del variant results in deletion of part of intron 9 of SLC6A8. RT-PCR analysis showed that this variant results in two abnormal splice products (intron 9 retention and skipping of exon 10) (PMID: 20717164) (PVS1_Moderate). This variant has been reported two unrelated males with intellectual disability, language delay, epilepsy, elevated urine creatine/creatinine ratio and a reduced creatine peak on brain MRS (PMID: 20717164, 20501887) (PP4_strong, PS4_supporting). Maternal testing of one proband was negative for the variant (PMID: 20717164) (PM6). The variant is absent in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_moderate, PP4_strong, PM6, PS4_supporting, PM2_supporting. (Classification approved by the ClinGen CCDS VCEP on April 25, 2024).

PP4_Strong

This variant has been reported in a male with intellectual disability, language delay, epilepsy, elevated urine creatine/creatinine ratio and a reduced creatine peak on brain MRS. Maternal testing for variant was negative (PMID: 20717164)

PVS1_Moderate

The NM_005629.4:c.1392+24_1393-30del variant results in deletion of part of intron 9 of SLC6A8. RT-PCR analysis showed that this variant results in two different splice products, r.[1392_1393ins1392+1_1393-1;1392+24_1393-30del (retention of intron 9, add 54 intronic nucleotides, in frame), and 1393_1495del (skipping of exon 10, 103 nucleotides, frameshift) (see Figure 4, PMID: 20717164).

PS4_Supporting

This variant has been reported two unrelated males with intellectual disability, language delay, epilepsy, elevated urine creatine/creatinine ratio and a reduced creatine peak on brain MRS (PMID: 20717164, 20501887)

PM2_Supporting

The variant is absent in gnomAD v2.1.1

PM6

Mother of proband did not have variant (PMID: 20717164)

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