Variant: NM_005629.4(SLC6A8):c.1072_1095del (p.Val358_Phe365del)

CA10603706

280226 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 4ad21784-b6c7-48a3-bc36-3bf8d7dee50d

Approved on: 2025-01-07

Published on: 2025-01-09

HGVS expressions

NM_005629.4:c.1072_1095del
NM_005629.4(SLC6A8):c.1072_1095del (p.Val358_Phe365del)
NC_000023.11:g.153693517_153693540del
CM000685.2:g.153693517_153693540del
NC_000023.10:g.152958972_152958995del
CM000685.1:g.152958972_152958995del
NC_000023.9:g.152612166_152612189del
NG_012016.1:g.10221_10244del
NG_012016.2:g.10221_10244del
ENST00000253122.10:c.1072_1095del
ENST00000253122.9:c.1072_1095del
ENST00000413787.1:c.188_211del
ENST00000430077.6:c.727_750del
ENST00000442457.1:c.126_149del
ENST00000457723.1:c.56_79del
ENST00000467402.1:n.171_194del
ENST00000485324.1:n.1105_1128del
NM_001142805.1:c.1042_1065del
NM_001142806.1:c.727_750del
NM_005629.3:c.1072_1095del
NM_001142805.2:c.1042_1065del

Uncertain Significance

• Met criteria codes: PP4 PM4 PM2_Supporting

• Not Met criteria codes: BP4 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:c.1072_1095del variant in SLC6A8 is a deletion of 24 nucleotides within exon 7 of the SLC6A8 gene and is predicted to lead to the deletion of 8 amino acids (p.Val358_Phe365del) (PM4). This variant has been previously reported in one hemizygous individual with elevated urinary creatine/creatinine (PMID: 34050321) (PP4). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). The in silico predictor MutPred-Indel gives a score of 0.85553 (>0.70 suggests that the variant is deleterious with a false positive rate of 5%), but MutationTaster predicts that the variant is a "polymorphism". Due to conflicting results, neither PP3 nor BP4 is met).There is a ClinVar entry for this variant (Variation ID: 280226). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM4, PP4, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 7, 2025)

Met criteria codes

• PP4: This variant has been previously reported in one hemizygous individual with elevated urinary creatine/creatinine (PMID: 34050321) (PP4).
• PM4: The NM_005629.4:c.1072_1095del variant in SLC6A8 is a deletion of 24 nucleotides within exon 7 of the SLC6A8 gene and is predicted to lead to the deletion of 8 amino acids (p.Val358_Phe365del) (PM4).
• PM2_Supporting: This variant is absent in gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• BP4: The in silico predictor MutPred-Indel gives a score of 0.85553 (>0.70 suggests that the variant is deleterious with a false positive rate of 5%), but MutationTaster predicts that the variant is a "polymorphism". Due to conflicting results, neither PP3 nor BP4 is met.
• PP3: The in silico predictor MutPred-Indel gives a score of 0.85553 (>0.70 suggests that the variant is deleterious with a false positive rate of 5%), but MutationTaster predicts that the variant is a "polymorphism". Due to conflicting results, neither PP3 nor BP4 is met.