rs587776760
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000387.6(SLC25A20):βc.84delβ(p.His29ThrfsTer100) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,606,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
SLC25A20
NM_000387.6 frameshift
NM_000387.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.144
Genes affected
SLC25A20 (HGNC:1421): (solute carrier family 25 member 20) This gene product is one of several closely related mitochondrial-membrane carrier proteins that shuttle substrates between cytosol and the intramitochondrial matrix space. This protein mediates the transport of acylcarnitines into mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. Mutations in this gene are associated with carnitine-acylcarnitine translocase deficiency, which can cause a variety of pathological conditions such as hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and is usually lethal in new born and infants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 32 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 3-48898710-GA-G is Pathogenic according to our data. Variant chr3-48898710-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 12136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A20 | NM_000387.6 | c.84del | p.His29ThrfsTer100 | frameshift_variant | 1/9 | ENST00000319017.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A20 | ENST00000319017.5 | c.84del | p.His29ThrfsTer100 | frameshift_variant | 1/9 | 1 | NM_000387.6 | P1 | |
SLC25A20 | ENST00000430379.5 | c.84del | p.His29ThrfsTer87 | frameshift_variant | 1/7 | 3 | |||
SLC25A20 | ENST00000440964.1 | c.84del | p.His29ThrfsTer12 | frameshift_variant, NMD_transcript_variant | 1/10 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000424 AC: 1AN: 236062Hom.: 0 AF XY: 0.00000778 AC XY: 1AN XY: 128578
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GnomAD4 exome AF: 0.00000550 AC: 8AN: 1454508Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5AN XY: 723132
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74382
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carnitine acylcarnitine translocase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2022 | Variant summary: SLC25A20 c.84delT (p.His29ThrfsX100) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.2e-06 in 236062 control chromosomes (gnomAD). c.84delT has been reported in the literature in individuals affected with Carnitine-Acylcarnitine Translocase Deficiency (e.g. Ogawa_2000, Hsu_2001). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2023 | This sequence change creates a premature translational stop signal (p.His29Thrfs*100) in the SLC25A20 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A20 are known to be pathogenic (PMID: 25614308). This variant is present in population databases (rs587776760, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with carnitine-acylcarnitine translocase deficiency (PMID: 10697964, 11592821). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 120delT and 146delT. ClinVar contains an entry for this variant (Variation ID: 12136). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2014 | The c.84delT mutation in the SLC25A20 gene has been reported previously in association with carnitine-acylcarnitine translocase (CACT) deficiency using alternate nomenclature (Ogawa et al., 2000). The deletion causes a frameshift starting with codon Histidine 29, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 100 of the new reading frame, denoted p.His29ThrfsX100. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in SLC25A20 panel(s). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at