Variant: NM_005629.4(SLC6A8):c.1661C>T (p.Pro554Leu)

CA345036

65693 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 3c251870-1145-4f3d-b6c8-a8eafb2d9656

Approved on: 2025-01-07

Published on: 2025-01-09

HGVS expressions

NM_005629.4:c.1661C>T
NM_005629.4(SLC6A8):c.1661C>T (p.Pro554Leu)
NC_000023.11:g.153694783C>T
CM000685.2:g.153694783C>T
NC_000023.10:g.152960238C>T
CM000685.1:g.152960238C>T
NC_000023.9:g.152613432C>T
NG_012016.1:g.11487C>T
NG_012016.2:g.11487C>T
ENST00000253122.10:c.1661C>T
ENST00000253122.9:c.1661C>T
ENST00000430077.6:c.1316C>T
ENST00000485324.1:n.1968C>T
NM_001142805.1:c.1631C>T
NM_001142806.1:c.1316C>T
NM_005629.3:c.1661C>T
NM_001142805.2:c.1631C>T

Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PP3 PP1_Moderate PP4_Strong

• Not Met criteria codes: PS3

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.1661C>T variant in SLC6A8 is predicted to result in the substitution of proline by leucine at amino acid 554 (p.Pro554Leu). This variant has been reported in a hemizygous male with clinical features consistent with creatine transporter deficiency, elevated urine creatine/creatinine ratio, and deficient creatine uptake in fibroblasts (PMID: 15690373, 21556832, 24789340) (PP4_Strong). This variant has also been reported in another 4 unrelated probands, all with clinical features consistent with creatine transporter deficiency. Two of these individuals (one male, one female) have biochemical and/or brain magnetic resonance spectroscopy (MRS) data to support the diagnosis (PMID: 15154114, 17465020, 21836662; 33164824) (PS4_Moderate). Supportive biochemical, MRS, or creatine uptake results are not available for the other two patients (PMID: 23660394, 30293248). One proband has an affected brother, with elevated creatine/creatinine ratio in urine and deficient creatine transport in fibroblasts; their mother is heterozygous for the variant and has mild learning difficulties (PMID: 15690373) (2 segregations, PP1_Moderate). Segregation of the clinical symptoms with the variant has been reported in other families, but no biochemical, MRS, or creatine uptake studies were performed in the affected individuals and, therefore, this data will not be counted towards PP1 (PMID: 15154114 - 5 segregations; PMID: 33164824). The variant is not in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Overexpression of the variant in SLC6A8-deficient fibroblasts did not result in a significant increase in creatine transport. Studies were carried out with 500uM creatine (PMID: 17465020). The CCDS VCEP requires that studies are carried out with <125uM creatine. Therefore, PS3 is not met. The computational predictor REVEL gives a score of 0.937 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variant ID: 65693). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PS4_Moderate, PP1_Moderate, PP3, PM2_Supporting. )Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on Jan 7, 2025).

Met criteria codes

• PS4_Moderate: This variant has been reported in 5 unrelated probands, all with clinical features consistent with creatine transporter deficiency. Three of these individuals (two male, one female) have biochemical, brain magnetic resonance spectroscopy (MRS), and/or fibroblast creatine uptake data to support the diagnosis (PMID: 15690373, 21556832, 24789340; 15154114, 17465020, 21836662; 33164824) (PP4_Strong, PS4_Moderate). Supportive biochemical, MRS, or creatine uptake results are not available for the other two patients (PMID: 23660394, 30293248).
• PM2_Supporting: The variant is not in gnomAD v2.1.1. or v4.1.0. (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.937 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). SpliceAI predicts that the variant has no impact on splicing.
• PP1_Moderate: One proband has an affected brother, with elevated creatine/creatinine ratio in urine and deficient creatine transport in fibroblasts; their mother is heterozygous for the variant and has mild learning difficulties (PMID: 15690373) (2 segregations, PP1_Moderate). Segregation of the clinical symptoms with the variant has been reported in other families, but no biochemical, MRS, or creatine uptake studies were performed in the affected individuals and, therefore, this data will not be counted towards PP1 (PMID: 15154114 - 5 segregations; PMID: 33164824).
• PP4_Strong: This variant has been reported in a hemizygous male with clinical features consistent with creatine transporter deficiency, elevated urine creatine/creatinine ratio, and deficient creatine uptake in fibroblasts (PMID: 15690373, 21556832, 24789340) (PP4_Strong).

Not Met criteria codes

• PS3: Overexpression of the variant in SLC6A8-deficient fibroblasts did not result in a significant increase in creatine transport. Studies were carried out with 500uM creatine (PMID: 17465020). The CCDS VCEP requires that studies are carried out with <125uM creatine. Therefore, PS3 is not met.