Variant: NM_005629.4(SLC6A8):c.1262G>A (p.Gly421Asp)

CA415086679

427187 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 92594041-d448-4913-9a45-a97bdb82a02f

Approved on: 2025-01-09

Published on: 2025-01-09

HGVS expressions

NM_005629.4:c.1262G>A
NM_005629.4(SLC6A8):c.1262G>A (p.Gly421Asp)
NC_000023.11:g.153694137G>A
CM000685.2:g.153694137G>A
NC_000023.10:g.152959592G>A
CM000685.1:g.152959592G>A
NC_000023.9:g.152612786G>A
NG_012016.1:g.10841G>A
NG_012016.2:g.10841G>A
ENST00000253122.10:c.1262G>A
ENST00000253122.9:c.1262G>A
ENST00000413787.1:c.258-67G>A
ENST00000430077.6:c.917G>A
ENST00000442457.1:c.316G>A
ENST00000457723.1:c.239G>A
ENST00000485324.1:n.1407G>A
NM_001142805.1:c.1232G>A
NM_001142806.1:c.917G>A
NM_005629.3:c.1262G>A
NM_001142805.2:c.1232G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BP4 PP3 PM5

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.1262G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a glycine for an aspartate at amino acid position 421 (p.Gly421Asp). To our knowledge, this variant has not been reported in the literature and no functional studies are available. This variant is absent in gnomAD v4.0.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.585, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 427187). 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): PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 9, 2025)

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v4.1.0. (PM2_Supporting).

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.585, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. SpliceAI suggests that the variant has no impact on splicing (score of 0.28 for "acceptor loss" but variant is not at accepter splice site).
• PP3: The computational predictor REVEL gives a score of 0.585, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met.
• PM5: c.1261G>C (p.Gly421Arg) is classified as a VUS in ClinVar