Variant: NM_005629.4(SLC6A8):c.354C>T (p.Ala118=)

CA519184963

511340 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 858ee93e-b99e-4afd-be05-3714f54f74b6

Approved on: 2022-06-06

Published on: 2022-10-08

HGVS expressions

NM_005629.4:c.354C>T
NM_005629.4(SLC6A8):c.354C>T (p.Ala118=)
NC_000023.11:g.153690466C>T
CM000685.2:g.153690466C>T
NC_000023.10:g.152955921C>T
CM000685.1:g.152955921C>T
NC_000023.9:g.152609115C>T
NG_012016.1:g.7170C>T
NG_012016.2:g.7170C>T
ENST00000253122.10:c.354C>T
ENST00000675713.1:n.108C>T
ENST00000253122.9:c.354C>T
ENST00000430077.6:c.9C>T
ENST00000476466.1:n.206C>T
NM_001142805.1:c.354C>T
NM_001142806.1:c.9C>T
NM_005629.3:c.354C>T
NM_001142805.2:c.354C>T

Likely Benign

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

• Met criteria codes: BP4 BP7 PM2_Supporting

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.354C>T (p.Ala118=) variant in SLC6A8 is a synonymous (silent) variant that is not predicted by SpliceAI or varSEAK to impact splicing, and it occurs at a nucleotide that is not conserved (BP4, BP7). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in any patients with creatine transporter deficiency in the literature. There is a ClinVar entry for this variant (Variation ID: 511340). 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 applied, as specified by the ClinGen LSD VCEP (specifications version 1.1.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• BP4: The computational predictors SpliceAI and varSEAK predict that the variant has no impact on splicing (BP4).
• BP7: The computational predictors SpliceAI and varSEAK predict that the variant has no impact on splicing, and the nucelotide is not highly conserved (BP7).
• PM2_Supporting: The variant is absent in gnomAD v2.1.1 (PM2_Supporting).