rs122453113
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_SupportingPVS1_StrongPP1_StrongPP4_Strong
This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1540C>T (p.Arg514Ter) variant in SLC6A8 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 11/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). A male patient has been reported with almost complete absence of the creatine signal on brain MRS, elevated creatine in urine, and virtually undetectable creatine transport in fibroblasts (PMID:11326334) (PP4_Strong). The mother, maternal aunt, and maternal grandmother are all heterozygous for the variant and all have evidence of creatine transporter deficiency. The paternal uncle has severe intellectual disability but was unavailable for study (PMID:11326334) (PP1_Strong). 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 Cerebral creatine Deficiencies Variant Curation Expert Panel CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP1_Strong, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256009/MONDO:0010305/027
Frequency
Consequence
NM_005629.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC6A8 | NM_005629.4 | c.1540C>T | p.Arg514Ter | stop_gained | 11/13 | ENST00000253122.10 | |
SLC6A8 | NM_001142805.2 | c.1510C>T | p.Arg504Ter | stop_gained | 11/13 | ||
SLC6A8 | NM_001142806.1 | c.1195C>T | p.Arg399Ter | stop_gained | 11/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC6A8 | ENST00000253122.10 | c.1540C>T | p.Arg514Ter | stop_gained | 11/13 | 1 | NM_005629.4 | P1 | |
SLC6A8 | ENST00000430077.6 | c.1195C>T | p.Arg399Ter | stop_gained | 11/13 | 2 | |||
SLC6A8 | ENST00000485324.1 | n.1847C>T | non_coding_transcript_exon_variant | 4/6 | 2 | ||||
SLC6A8 | ENST00000413787.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000914 AC: 1AN: 109403Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 31769
GnomAD4 exome Cov.: 34
GnomAD4 genome ? AF: 0.00000914 AC: 1AN: 109446Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 31822
ClinVar
Submissions by phenotype
Creatine transporter deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11696). This premature translational stop signal has been observed in individual(s) with creatine transporter deficiency (PMID: 11326334, 12536364). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg514*) 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). - |
Pathogenic, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Oct 13, 2023 | The NM_005629.4:c.1540C>T (p.Arg514Ter) variant in SLC6A8 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 11/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). A male patient has been reported with almost complete absence of the creatine signal on brain MRS, elevated creatine in urine, and virtually undetectable creatine transport in fibroblasts (PMID: 11326334) (PP4_Strong). The mother, maternal aunt, and maternal grandmother are all heterozygous for the variant and all have evidence of creatine transporter deficiency. The paternal uncle has severe intellectual disability but was unavailable for study (PMID: 11326334) (PP1_Strong). 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 Cerebral creatine Deficiencies Variant Curation Expert Panel CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP1_Strong, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 27, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | Nonsense 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16738945, 34800434, 11326334, 27081545, 24137762, 20528887, 23644449, 20846889, 10893433, 24190795, 15234334, 28065824, 16143026, 12536364, 12544242, 16763899, 15154114, 31031587) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2018 | The p.R514* pathogenic mutation (also known as c.1540C>T), located in coding exon 11 of the SLC6A8 gene, results from a C to T substitution at nucleotide position 1540. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation was detected in a male individual with creatine-deficiency syndrome as well as in two of his female relatives with mild biochemical abnormalities and learning disabilities (Salomons GS et al. Am. J. Hum. Genet., 2001 Jun;68:1497-500). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Apr 20, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at