Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002867043 | SCV004227935 | pathogenic | Creatine transporter deficiency | 2023-12-14 | reviewed by expert panel | curation | The NM_005629.4(SLC6A8):c.1136_1137del (p.Glu379fs) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 7/13, and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. There is a ClinVar entry for this variant (Variation ID:2031214, Pathogenic/Likely Pathogenic, 2 stars) with 3 submissions. This variant is absent in population databases (PM2_Supporting). The p.Glu379fs variant was reported in one 8y male with severe intellectual disability, cerebral atrophy and hypotonia. Patient had elevated urine creatine:creatinine ratio 4471 (21–1143 mmol/mol creatinine). H-MRS demonstrated a partially absent creatine peak, meeting criteria for PP4_Strong [PMID:3789175]. The p.Glu379fs variant was also reported in an independent case, a male with global developmental delay, epilepsy, broad based gait, and autistic behavior with elevated creatine:creatine ratio (3.46mmol/mmol creatine, normal 0.005-1.07) and significantly reduced creatine peak on H-MRS. The variant was identified de novo in this individual [PMID:3789175]. In summary, this variant meets the criteria to be classified as Pathogenic 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): PVS1, PS2, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on December 14, 2023). |
| Labcorp Genetics |
RCV002867043 | SCV003240448 | pathogenic | Creatine transporter deficiency | 2022-09-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu379Valfs*85) in the SLC6A8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with creatine transporter deficiency (PMID: 29435807). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002867044 | SCV003556433 | pathogenic | Inborn genetic diseases | 2021-06-16 | criteria provided, single submitter | clinical testing | The c.1136_1137delAG (p.E379Vfs*85) alteration, located in exon 7 (coding exon 7) of the SLC6A8 gene, consists of a deletion of 2 nucleotides from position 1136 to 1137, causing a translational frameshift with a predicted alternate stop codon after 85 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the SLC6A8 c.1136_1137delAG alteration was not observed, with coverage at this position. This mutation was reported in a male with SLC6A8-related cerebral creatine deficiency syndrome (Bruun, 2018). Based on the available evidence, this alteration is classified as pathogenic. |
| Revvity Omics, |
RCV002867043 | SCV003815289 | likely pathogenic | Creatine transporter deficiency | 2022-08-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV004786759 | SCV005401696 | pathogenic | not provided | 2024-05-01 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37891751, 29435807) |