Variant: NM_001142805.2:c.1016+21_1016+54del

CA2579916736

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: e2648cb3-8d22-4324-b167-35a7b32c733c

Approved on: 2023-08-08

Published on: 2024-06-24

HGVS expressions

NM_001142805.2:c.1016+21_1016+54del
NC_000023.11:g.153693387_153693420del
CM000685.2:g.153693387_153693420del
NC_000023.10:g.152958842_152958875del
CM000685.1:g.152958842_152958875del
NC_000023.9:g.152612036_152612069del
NG_012016.1:g.10091_10124del
NG_012016.2:g.10091_10124del
ENST00000253122.10:c.1016+21_1017-42del
ENST00000253122.9:c.1016+21_1017-42del
ENST00000413787.1:c.162+21_162+54del
ENST00000430077.6:c.671+21_672-42del
ENST00000442457.1:c.100+21_100+54del
ENST00000467402.1:n.146-105_146-72del
ENST00000485324.1:n.1049+21_1050-42del
NM_001142805.1:c.1016+21_1016+54del
NM_001142806.1:c.671+21_672-42del
NM_005629.3:c.1016+21_1017-42del
NM_005629.4:c.1016+21_1017-42del

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4_Strong

• Not Met criteria codes: PP3

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(SLC6A8):c.1016+21_1017-42del variant in SLC6A8 is an intronic deletion of 34 nucleotides within intron 6/12. This variant is also referred to as c.1016+11_1017-52del in literature based on genome build GRCh36. This variant is absent from gnomAD v3.1.2, therefore PM2_Supporting criteria is applicable. The computational predictor SpliceAI gives delta scores of 0.07 (donor loss, -10bp) and acceptor loss 0.01 (acceptor loss, -49bp) which is not highly suggestive of a splicing defect. This variant has not been previously reported in ClinVar, although has been reported in an affected male in the literature with hypotonia, motor delay, speech delay and seizures [PMID:27081545]. This individual was found to have elevated Cr/Crn ratio on two different days with elevated ratio (2.66, 4.56 with reference value <1.5), H-MRS demonstrating marked reduction of the creatine peak in this individual, and creatine uptake assayed in fibroblasts with Cr concentrations of 25 and 500uM, at 25uM the creatine uptake was undetectable and at 500uM creatine uptake was <25% of normal cells. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance 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): PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on August 8, 2023)

Met criteria codes

• PM2_Supporting: The NM_005629.4(SLC6A8):c.1016+11_1017-52del variant in SLC6A8 is absent from gnomAD v3.1.2, therefore PM2_Supporting criteria is applicable.
• PP4_Strong: The NM_005629.4(SLC6A8):c.1016+11_1017-52del variant in SLC6A8 has been reported in an affected male in the literature with hypotonia, motor delay, speech delay and seizures [PMID:27081545]. This individual was found to have elevated Cr/Crn ratio on two different days with elevated ratio (2.66, 4.56 with reference value <1.5), H-MRS demonstrating marked reduction of the creatine peak in this individual, and creatine uptake assayed in fibroblasts with Cr concentrations of 25 and 500uM, at 25uM the creatine uptake was undetectable and at 500uM creatine uptake was <25% of normal cells

Not Met criteria codes

• PP3: The computational predictor SpliceAI gives delta scores of 0.07 (donor loss, -10bp) and acceptor loss 0.01 (acceptor loss, -49bp) which is not highly suggestive of a splicing defect.