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Variant: NM_005629.4(SLC6A8):c.1631C>T (p.Pro544Leu)

CA345034

65692 (ClinVar)

Gene: SLC6A8
Condition: creatine transporter deficiency
Inheritance Mode: X-linked inheritance
UUID: 408b1446-5f61-4b15-8aaa-1b1215f979f0
Approved on: 2023-10-26
Published on: 2023-11-08

HGVS expressions

NM_005629.4:c.1631C>T
NM_005629.4(SLC6A8):c.1631C>T (p.Pro544Leu)
NC_000023.11:g.153694753C>T
CM000685.2:g.153694753C>T
NC_000023.10:g.152960208C>T
CM000685.1:g.152960208C>T
NC_000023.9:g.152613402C>T
NG_012016.1:g.11457C>T
NG_012016.2:g.11457C>T
ENST00000253122.10:c.1631C>T
ENST00000253122.9:c.1631C>T
ENST00000430077.6:c.1286C>T
ENST00000485324.1:n.1938C>T
NM_001142805.1:c.1601C>T
NM_001142806.1:c.1286C>T
NM_005629.3:c.1631C>T
NM_001142805.2:c.1601C>T
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Likely Pathogenic

Met criteria codes 5
PP3 PM6 PS4_Supporting PP4_Strong PM2_Supporting
Not Met criteria codes 2
PS3 PP1

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.1631C>T in SLC6A8 is a missense variant predicted to cause substitution of Proline with Leucine (p.Pro544Leu) at amino acid 544 in the 12th of 13 exons. This variant is absent from gnomAD v2.1.1, (PM2_Supporting). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). This variant was reported in a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. Urine analysis showed an increased creatine/creatinine ratio (1.83; n.v. 0.03–0.92) with normal guanidinoacetate/creatinine ratio (0.024; n.v. 0.023–0.214) (1 point). Brain MRI with angiography and perfusion study was normal, while 1H-MRS revealed a consistent decrease in the creatine peak (Fig. 2) (3 points). Full sequencing of the SLC6A8 gene was reported. (PMID:17553121) (PP4_Strong). This variant was reported in a proband with an increased urine creatine/creatinine ratio of 2.0 (normal range 0.017–0.72), the proband’s brother also was affected and had elevated urine ratios and was hemizygous for the variant, while their mother was heterozygous for the same variant (PMID: 15690373). (PS4_Supporting). A female proband presented with learning disabilities, seizures and significantly reduced creatine by 1 H-MRS (fig. 1). The patient had normal urine creatine/creatinine ratio (0.38 mmol/mmol). Molecular genetic testing identified the heterozygous variant SLC6A8 (c.1631C>T, p.(Pro544Leu)). Segregation analysis including both parents revealed that the variant was de novo in the patient (PMID: 37708665) (PM6). This variant was assessed for co-segregation evidence (PP1) and functional evidence (PS3), but in both cases did not meet the specifications (PP1_Not Met, PS3_Not Met). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant 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 1.1.0). PM2_Supporting, PP3, PP4_Strong, PS4_Supporting, PM6. (Classification approved by the ClinGen CCDS VCEP on Oct. 26, 2023)
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3).
PM6
A female proband presented with learning disabilities, seizures and significantly reduced creatine by 1 H-MRS (fig. 1). The patient had normal urine creatine/creatinine ratio (0.38 mmol/mmol). Molecular genetic testing identified the heterozygous variant SLC6A8 (c.1631C>T, p.(Pro544Leu)). Segregation analysis including both parents revealed that the variant was de novo in the patient (PMID: 37708665) (PM6).
PS4_Supporting
This variant was reported in a proband with an increased urine creatine/creatinine ratio of 2.0 (normal range 0.017–0.72) (PMID: 15690373). (PS4_Supporting).
PP4_Strong
This variant was reported in a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. Urine analysis showed an increased creatine/creatinine ratio (1.83; n.v. 0.03–0.92) with normal guanidinoacetate/creatinine ratio (0.024; n.v. 0.023–0.214) (1 point). Brain MRI with angiography and perfusion study was normal, while 1H-MRS revealed a consistent decrease in the creatine peak (Fig. 2) (3 points). Full sequencing of the SLC6A8 was reported. (PMID:17553121) (PP4_Strong).
PM2_Supporting
This variant is absent from gnomAD v2.1.1, meeting criteria for PM2_Supporting.
Not Met criteria codes
PS3
The creatine uptake capacity of this variant was assessed in multiple studies (PMIDs: 22281021, 21556832, 15690373). In all cases it was measured as reduced compared to wild-type, however none of the studies meet the <10% reduction from wild-type required by the Cerebral Creatine Deficiency Variant Curation Expert Panel's specifications. (PS3_not met)
PP1
This variant has been reported in two brothers with elevated urine creatine/creatinine ratios. Their mother was heterozygous for the same variant, however no non-segregations were reported, and the decision was made to evaluate PP1 as not met (PMID:15690373).
Curation History
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