Variant: NM_005629.4(SLC6A8):c.619C>T (p.Arg207Trp)

CA415079397

1211026 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 3ea40681-dff3-4b07-8d6e-dcccecaf824d

Approved on: 2023-03-09

Published on: 2023-03-09

HGVS expressions

NM_005629.4:c.619C>T
NM_005629.4(SLC6A8):c.619C>T (p.Arg207Trp)
NC_000023.11:g.153691528C>T
CM000685.2:g.153691528C>T
NC_000023.10:g.152956983C>T
CM000685.1:g.152956983C>T
NC_000023.9:g.152610177C>T
NG_012016.1:g.8232C>T
NG_012016.2:g.8232C>T
ENST00000253122.10:c.619C>T
ENST00000675713.1:n.373C>T
ENST00000253122.9:c.619C>T
ENST00000429147.1:n.68C>T
ENST00000430077.6:c.274C>T
ENST00000466243.1:n.411C>T
ENST00000467402.1:n.145+21C>T
NM_001142805.1:c.619C>T
NM_001142806.1:c.274C>T
NM_005629.3:c.619C>T
NM_001142805.2:c.619C>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PS3_Supporting PP4_Strong PM2_Supporting

• Not Met criteria codes: PP1 PP3 BP4

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.619C>T (p.Arg207Trp) variant in SLC6A8 is a missense variant predicted to result in the substitution of arginine by tryptophan at amino acid 207 (p.Arg207Trp). One male patient has been described with this variant and with clinical symptoms consistent with creatine transporter deficiency, absent creatine peak on MRS, elevated creatine in urine, and <10% creatine uptake in fibroblasts (PP4_Strong). His mother was confirmed to be heterozygous, "low functioning" and with normal urine creatine. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). When expressed in HeLa cells, the variant resulted in impaired creatine transport with 2 mM unlabeled substrate (PMID: 27408820). Based on review of this data by the ClinGen CCDS VCEP, this data meets PS3_Supporting. The computational predictor REVEL gives a score of 0.578 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. There is a ClinVar entry for this variant (Variation ID: 211026). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications version 1.1.0): PP4_Strong, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on March 9, 2023).

Met criteria codes

• PS3_Supporting: When expressed in HeLa cells, the variant resulted in impaired creatine transport with 2 mM unlabeled substrate (PMID: 27408820). Based on review of this data by the ClinGen CCDS VCEP, this data meets PS3_Supporting.
• PP4_Strong: One male patient has been described with this variant and with clinical symptoms consistent with creatine transporter deficiency, absent creatine peak on MRS, elevated creatine in urine, and <10% creatine uptake in fibroblasts (with 2mM creatine) (PMID: 27408820) (PP4_Strong).
• PM2_Supporting: The variant is not in gnomAD v2.1.1. (PM2_Supporting).

Not Met criteria codes

• PP1: Mother of affected male was confirmed to be heterozygous for the variant, "low functioning" and with normal urine creatine (PMID: 27408820). Insufficient segregations to apply PP1.
• PP3: The computational predictor REVEL gives a score of 0.578 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function.
• BP4: The computational predictor REVEL gives a score of 0.578 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function.