Variant: NM_005629.4(SLC6A8):c.681G>A (p.Val227=)

CA519186681

669127 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 5583c02d-44a2-4a3e-bd58-49b0305b7089

Approved on: 2022-06-06

Published on: 2022-10-08

HGVS expressions

NM_005629.4:c.681G>A
NM_005629.4(SLC6A8):c.681G>A (p.Val227=)
NC_000023.11:g.153692011G>A
CM000685.2:g.153692011G>A
NC_000023.10:g.152957466G>A
CM000685.1:g.152957466G>A
NC_000023.9:g.152610660G>A
NG_012016.1:g.8715G>A
NG_012016.2:g.8715G>A
ENST00000253122.10:c.681G>A
ENST00000675713.1:n.435G>A
ENST00000253122.9:c.681G>A
ENST00000429147.1:n.130G>A
ENST00000430077.6:c.336G>A
ENST00000466243.1:n.473G>A
ENST00000467402.1:n.145+504G>A
NM_001142805.1:c.681G>A
NM_001142806.1:c.336G>A
NM_005629.3:c.681G>A
NM_001142805.2:c.681G>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BP7 BP4 PM2_Supporting

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.681G>A (p.Val227=) variant in SLC6A8 is a synonymous (silent) variant that is not predicted to impact splicing and the nucleotide is not well conserved (BP4, BP7). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 669127). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• BP7: The NM_005629.4:c.681G>A (p.Val227=) variant in SLC6A8 is a synonymous (silent) variant that is not predicted to impact splicing, and the nuclelotide is not well conserved (BP7).
• BP4: The computational tools SpliceAI and varSEAK predict that the variant has no impact on splicing.
• PM2_Supporting: This variant is absent in gnomAD v2.1.1. (PM2_Supporting).