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]

Variant: NM_005629.4(SLC6A8):c.1016+2T>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA415085022

520792 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: d1b0dc33-84ec-4eaa-82ce-49bfdd9b45b9

Approved on: 2023-02-23

Published on: 2023-03-09

HGVS expressions

NM_005629.4:c.1016+2T>C

NM_005629.4(SLC6A8):c.1016+2T>C

NC_000023.11:g.153693368T>C

CM000685.2:g.153693368T>C

NC_000023.10:g.152958823T>C

CM000685.1:g.152958823T>C

NC_000023.9:g.152612017T>C

NG_012016.1:g.10072T>C

NG_012016.2:g.10072T>C

ENST00000253122.10:c.1016+2T>C

ENST00000253122.9:c.1016+2T>C

ENST00000413787.1:n.162+2T>C

ENST00000430077.6:c.671+2T>C

ENST00000442457.1:n.100+2T>C

ENST00000467402.1:n.146-124T>C

ENST00000485324.1:n.1049+2T>C

NM_001142805.1:c.1016+2T>C

NM_001142806.1:c.671+2T>C

NM_005629.3:c.1016+2T>C

NM_001142805.2:c.1016+2T>C

Pathogenic

PP4 PVS1 PM2_Supporting

PS4

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.1016+2T>C variant occurs within the canonical splice donor of intron 6 of SLC6A8. It is predicted to cause skipping of biologically-relevant-exon 6/13, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two male patients have been reported who are hemizygous for the variant (presumed to be different cases). One of these patients has profound intellectual disability, seizures, and elevated urine creatine/creatinine ratio (PMID 16738945) (PP4). There was "clinical suspicion" for a CCDS for the other patient., but results of follow up biochemical testing or brain magnetic resonance spectrscopy are not available (PMID 23660394). There is a ClinVar entry for this variant (Variation ID: 520792). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Verions 1.1.0): PVS1, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 23, 2023).

PP4

Two male patients have been reported who are hemizygous for the variant (presumed to be different cases). One of these patients has profound intellectual disability, seizures, and elevated and urine creatine/creatinine ratio (1.4; normal range 0.01–0.53). No brain MRS results are available (PMID 16738945). There was "clinical suspicion" for a CCDS for the other patient. However, results of urine creatine level and brain MRS are not available (PMID 23660394). Based on the data from the first patient, PP4 is met.

PVS1

The NM_005629.4:c.1016+2T>C is a nucleotide substitution in the donor splice site of exon 6 of SLC6A8. To our knowledge, the results of functional, to assess the impact of this variant on splicing, are not available. If the variant results in skipping of exon 6, as predicted, the reading frame would be altered, meeting PVS1. Note that the SpliceAI score for donor loss is only 0.4 but varSEAK predicts an "effect on splicing" (Class 5) with loss of the splice site and exon skipping.

PM2_Supporting

This variant is not in gnomAD v2.1.1 (PM2_Supporting).

PS4

While 2 individuals with this variant have been reported (PMID: 16738945, 23660394), biochemical data is only available for one of them (PMID: 16738945) Therefore, PS4 is not met at the current time.

Curation History

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