Variant: NM_005629.4(SLC6A8):c.778-8C>G

CA10549325

511341 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 108dbf72-47c4-4dd5-a63f-e049358dafa7

Approved on: 2024-11-08

Published on: 2024-11-13

HGVS expressions

NM_005629.4:c.778-8C>G
NM_005629.4(SLC6A8):c.778-8C>G
NC_000023.11:g.153693033C>G
CM000685.2:g.153693033C>G
NC_000023.10:g.152958488C>G
CM000685.1:g.152958488C>G
NC_000023.9:g.152611682C>G
NG_012016.1:g.9737C>G
NG_012016.2:g.9737C>G
ENST00000253122.10:c.778-8C>G
ENST00000253122.9:c.778-8C>G
ENST00000430077.6:c.433-8C>G
ENST00000467402.1:n.146-459C>G
ENST00000485324.1:n.803C>G
NM_001142805.1:c.778-8C>G
NM_001142806.1:c.433-8C>G
NM_005629.3:c.778-8C>G
NM_001142805.2:c.778-8C>G

Uncertain Significance

• Met criteria codes: BS1

• 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.778-8C>G variant in SLC6A8 is an intronic variant affecting a nucleotide within the consensus splice site of intron 4. To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00047 (9/19012 alleles) in the South Asian population and 13 hemizygotes across all populations (BS1). SpliceAI predicts possible alteration of splicing (score 0.21), less than the cutoff for PP3 (≥0.5) but less than the cutoff for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 511341, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; two submitters: likely benign; one submitter: benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024)

Met criteria codes

• BS1: In gnomAD v2.1.1, the highest population minor allele frequency is 0.00047 (9/19012 alleles) in the South Asian population and 13 hemizygotes across all populations (BS1).

Not Met criteria codes

• BP4: SpliceAI predicts possible alteration of splicing (score 0.21), less than the cutoff for PP3 (≥0.5) but less than the cutoff for BP4 (<0.2), such that neither of these criteria are met.
• PP3: SpliceAI predicts possible alteration of splicing (score 0.21), less than the cutoff for PP3 (≥0.5) but less than the cutoff for BP4 (<0.2), such that neither of these criteria are met.