The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_005629.4(SLC6A8):c.92C>T (p.Pro31Leu)

CA415076214

572616 (ClinVar)

Gene: SLC6A8
Condition: creatine transporter deficiency
Inheritance Mode: X-linked inheritance
UUID: 8aafb1ca-68a8-44a8-9d58-d716b2464eb6
Approved on: 2024-11-08
Published on: 2024-11-13

HGVS expressions

NM_005629.4:c.92C>T
NM_005629.4(SLC6A8):c.92C>T (p.Pro31Leu)
NC_000023.11:g.153688666C>T
CM000685.2:g.153688666C>T
NC_000023.10:g.152954121C>T
CM000685.1:g.152954121C>T
NC_000023.9:g.152607315C>T
NG_012016.1:g.5370C>T
NG_012016.2:g.5370C>T
ENST00000253122.10:c.92C>T
ENST00000253122.9:c.92C>T
ENST00000458354.5:c.-3+149G>A
ENST00000480693.1:n.64+149G>A
NM_001142805.1:c.92C>T
NM_005629.3:c.92C>T
NM_001142805.2:c.92C>T
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Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 1
PM2

Evidence Links 0

Expert Panel

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.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID: 31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). There is a ClinVar entry for this variant (Variation ID:572616). In summary, this 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): BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024)
Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.114 which is below the threshold of 0.2, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing (BP4).
Not Met criteria codes
PM2
In gnomAD v2.1.1, the highest population minor allele frequency is 0.0001300 (4/30763 alleles) in the European population with 1 hemizygote, which is >0.0002 and >1 hemizygote, therefore PM2_Supporting criteria is not applicable.
Curation History
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