Variant: NM_001142805.2:c.219del

CA2582131482

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: 70fdcb73-ad48-4f30-b0d7-e069c9fc4c82

HGVS expressions

NM_001142805.2:c.219del
NC_000023.11:g.153688793del
CM000685.2:g.153688793del
NC_000023.10:g.152954248del
CM000685.1:g.152954248del
NC_000023.9:g.152607442del
NG_012016.1:g.5497del
NG_012016.2:g.5497del
ENST00000253122.10:c.219del
ENST00000253122.9:c.219del
ENST00000458354.5:c.-3+22del
ENST00000476466.1:n.71del
ENST00000480693.1:n.64+22del
NM_001142805.1:c.219del
NM_005629.3:c.219del
NM_005629.4:c.219del

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PVS1

• Not Met criteria codes: PP1

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.219del (p.Asn74ThrfsTer23) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A 5 year old male, hemizygous for the variant, with clinical symptoms consistent with creatine transporter deficiency has been reported with very low creatine on brain MRS and elevated urine creatine (values not provided) (PMID: 18726626) (PP4_Moderate). His 7 year old sister is heterozygous for the variant, with mild intellectual disability and reduced creatine on brain MRS. Their mother is reported to be asymptomatic (insufficient evidence to apply PP1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024)

Met criteria codes

• PM2_Supporting: The variant is absent in gnomAD v2.1.1. (PM2_Supporting).
• PP4_Moderate: A 5 year old male, hemizygous for the variant, with clinical symptoms consistent with creatine transporter deficiency has been reported with very low creatine on brain MRS and elevated urine creatine (values not provided). His 7 year old sister is heterozygous with mild intellectual disability and reduced creatine on brain MRS (PMID: 18726626) (PP4_Moderate).
• PVS1: The NM_005629.4(SLC6A8):c.219del (p.Asn74ThrfsTer23) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• PP1: The mother of the two sibs reported in PMID: 18726626 is described as asymptomatic. N biochemical or MRS data is available, and family history is negative. Insufficient data to apply PP1.

Approved on: 2024-03-28

Published on: 2024-03-28