Variant: NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu)

CA415086073

533700 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: f3486af2-7767-4033-839e-e11126aebcdb

Approved on: 2022-12-08

Published on: 2024-02-11

HGVS expressions

NM_005629.4:c.1145C>T
NM_005629.4(SLC6A8):c.1145C>T (p.Pro382Leu)
NC_000023.11:g.153693908C>T
CM000685.2:g.153693908C>T
NC_000023.10:g.152959363C>T
CM000685.1:g.152959363C>T
NC_000023.9:g.152612557C>T
NG_012016.1:g.10612C>T
NG_012016.2:g.10612C>T
ENST00000253122.10:c.1145C>T
ENST00000253122.9:c.1145C>T
ENST00000413787.1:c.258-296C>T
ENST00000430077.6:c.800C>T
ENST00000442457.1:c.199C>T
ENST00000457723.1:c.129C>T
ENST00000467402.1:n.244C>T
ENST00000485324.1:n.1178C>T
NM_001142805.1:c.1115C>T
NM_001142806.1:c.800C>T
NM_005629.3:c.1145C>T
NM_001142805.2:c.1115C>T

Likely Pathogenic

• Met criteria codes: PP3 PP4_Strong PM2_Supporting

• Not Met criteria codes: PS4 PP2

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.1145C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 382 (p.Pro382Leu). This variant is absent from gnomADv2.1.1, and has been reported in two individuals in the literature. In one affected individual in the literature, the ratio of urine Creatine to Creatinine was >99th percentile of normal, and reduced creatine uptake in patient fibroblasts was reported. In silico predictor REVEL suggests this variant will have a damaging / pathogenic effect on the protein (score=0.906). There is a ClinVar entry for this variant (Variation ID: 533700, 1 star review status) with 5 submitters classifying the variant with conflicting interpretations (Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine transporter deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PP4_Strong, PM2_Supporting, PP3.

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.906 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function
• PP4_Strong: An 8-year old male with severe intellectual disability, speech delay, behavioral problems and epilepsy was reported. This individual had U-CrCrtR >99th percentile, and reduced creatine uptake in patient fibroblasts was reported
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: Two independent probands identified, however one of the reported individuals was identified in a large cohort of individuals with intellectual disability [PMID:33624935], and no detailed clinical information was available nor were there any biochemical studies performed to confirm Creatine Transporter Deficiency
• PP2: No constraint against missense variation