Variant: NM_005629.4(SLC6A8):c.1646A>C (p.Asn549Thr)

CA10549610

1012671 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 17fe7f86-4e00-4f23-b90b-e4c5b4f1f898

HGVS expressions

NM_005629.4:c.1646A>C
NM_005629.4(SLC6A8):c.1646A>C (p.Asn549Thr)
NC_000023.11:g.153694768A>C
CM000685.2:g.153694768A>C
NC_000023.10:g.152960223A>C
CM000685.1:g.152960223A>C
NC_000023.9:g.152613417A>C
NG_012016.1:g.11472A>C
NG_012016.2:g.11472A>C
ENST00000253122.10:c.1646A>C
ENST00000253122.9:c.1646A>C
ENST00000430077.6:c.1301A>C
ENST00000485324.1:n.1953A>C
NM_001142805.1:c.1616A>C
NM_001142806.1:c.1301A>C
NM_005629.3:c.1646A>C
NM_001142805.2:c.1616A>C

Likely Benign

• Met criteria codes: BS2 BP4

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.1646A>C (p.Asn549Thr)variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Asparagine at amino acid 549 (p.Asn549Thr). There is a ClinVar entry for this variant (Variation ID:1012671, conflicting interpretations) with classifications as Variant of Uncertain Significance (n=1), Likely Benign (n=2), and Benign (n=1). This variant is found with an allele frequency of 0.00006027 in gnomADv2.1.1 with 3 hemizygotes present in that population database. Given the presence of >2 hemizygotes in gnomADv2.1.1, BS2 is applicable for this variant. The computational predictor REVEL gives a score of 0.182 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable. At the time of this curation, this variant has not been reported in individuals with suspected Creatine Transporter Deficiency in the literature. In summary, this variant meets the criteria to be classified as Likely Benign 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): BS2, BP4 (Classification approved by the ClinGen CCDS VCEP on February 23, 2023)

Met criteria codes

• BS2: This variant is found with an allele frequency of 0.00006027 in gnomADv2.1.1 with 3 hemizygotes present in that population database. Given the presence of >2 hemizygotes in gnomADv2.1.1, BS2 is applicable for this variant.
• BP4: The computational predictor REVEL gives a score of 0.182 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable.

Approved on: 2023-02-23

Published on: 2023-03-09