Evidence Repository - Clinical Genome Resources

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Variant: NM_005629.4(SLC6A8):c.11A>G (p.Lys4Arg)

CA415075865

2138757 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: e35a57aa-8c1f-41e6-8da6-3c8632f5be9a

Approved on: 2024-01-11

Published on: 2024-03-25

HGVS expressions

NM_005629.4:c.11A>G

NM_005629.4(SLC6A8):c.11A>G (p.Lys4Arg)

NC_000023.11:g.153688585A>G

CM000685.2:g.153688585A>G

NC_000023.10:g.152954040A>G

CM000685.1:g.152954040A>G

NC_000023.9:g.152607234A>G

NG_012016.1:g.5289A>G

NG_012016.2:g.5289A>G

ENST00000253122.10:c.11A>G

ENST00000253122.9:c.11A>G

ENST00000458354.5:c.-3+230T>C

ENST00000480693.1:n.64+230T>C

NM_001142805.1:c.11A>G

NM_005629.3:c.11A>G

NM_001142805.2:c.11A>G

Uncertain Significance

PM2_Supporting BP4

BS3 PP4

Evidence Links 1

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.11A>G variant in SLC6A8 is predicted to result in the missense substitution of lysine by arginine at amino acid 4 (p.Lys4Arg). The variant has been reported in a 15 year old hemizygous male with intellectual disability. Results of urine creatine level, creatine level on brain MRS, and creatine uptake studies are not available. There is insufficient evidence to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). When the variant was expressed in SLC6A8-deficient fibroblasts and creatine uptake was measured, the variant was reported to be non-pathogenic (Table 2). Compared to empty vector, expression of the variant increased creatine transport about 5 times, and expression of wild type SLC6A8 increased creatine transport about 6 times. However, because the assay was performed with 500uM creatine, and not <125uM (as required by the ClinGen CCDS VCEP), BS3 is not met. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.2, evidence that does not predict a damaging effect on SLC6A8 function (BP4). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes applied, as specified by the ClinGen CCDS VCEP: PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on January 11, 2024)

PM2_Supporting

The variant is absent in gnomAD v2.1.1. In gnomAD v4.0., the highest population minor allele frequency is 0.00002093 (1/47770 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), and there are no hemizygotes, meeting this criterion (PM2_Supporting).

BP4

The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.2, evidence that does not predict a damaging effect on SLC6A8 function (BP4).

BS3

When the variant was expressed in SLC6A8-deficient fibroblasts and creatine uptake was measured, the variant was reported to be non-pathogenic (Table 2). Compared to empty vector, expression of the variant increased creatine transport about 5 times, and expression of wild type SLC6A8 increased creatine transport about 6 times. However, because the assay was performed with 500uM creatine, and not <125uM (as required by the ClinGen CCDS VCEP), BS3 is not met.

The variant was expressed in SLC6A8-deficient fibroblasts (from a hemizygote with a loss of function variant, p.Arg514Ter). Transfections and the creatine uptake assay of each variant was performed in triplicate (500 uM Cr). The variant was reported to be non-pathogenic because the lysine at position 4 is not conserved and based on the results of the creatine uptake assay (Table 2). Creatine uptake was increased from 5.1 pmol Cr/ug protein for empty vector to 23.5 pmol Cr/ug protein with the variant, and 29.3 23.5 pmol Cr/ug protein with wild type SLC6A8 (Fig 1). However, this assay does not meet the requirements of the ClinGen CCDS VCEP which states that creatine uptake assays must be performed at <125uM. PubMed:17465020

PP4

The variant has been reported in a 15 year old hemizygous male with intellectual disability. Results of urine creatine level, creatine level on brain MRS, and creatine uptake studies are not available. There is insufficient evidence to apply PP4.

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