rs1553998199
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004168.4(SDHA):c.688delG(p.Glu230fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
SDHA
NM_004168.4 frameshift
NM_004168.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.50
Genes affected
SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 5-228247-TG-T is Pathogenic according to our data. Variant chr5-228247-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 472291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.688delG | p.Glu230fs | frameshift_variant | 6/15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.688delG | p.Glu230fs | frameshift_variant | 6/15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.688delG | non_coding_transcript_exon_variant | 6/24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461562Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727112
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Paragangliomas 5 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 13, 2019 | This particular SDHA variant, c.688delG, is predicted to cause a frameshift and subsequent premature stop codon (p.Glu230SerfsTer10) leading to a shortened or absent protein. It is not present in population databases (e.g., gnomAD). It has been reported in the heterozygous state in an individual with a gastric intestinal stromal tumor (PMID: 22955521). It is considered a likely pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jan 29, 2019 | This frameshifting variant in exon 6 of 15 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been reported twice in ClinVar by two different clinical labs as a pathogenic variant in patients with Paragangliomas 5 and Hereditary cancer-predisposing syndrome (ClinVar Accession IDs: RCV000551986.1; RCV000566076.1). This variant has also been previously reported in the literature as a germline heterozygous variant in an individual with gastrointestinal stromal tumor (GIST) (PMID: 22955521). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.688delG (p.Glu230SerfsTer10) variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 07, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 26, 2021 | - - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Glu230Serfs*10) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with gastrointestinal stromal tumor (PMID: 22955521). ClinVar contains an entry for this variant (Variation ID: 472291). For these reasons, this variant has been classified as Pathogenic. - |
Dilated cardiomyopathy 1GG Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2024 | 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: 34363016, 22955521) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2021 | The c.688delG pathogenic mutation, located in coding exon 6 of the SDHA gene, results from a deletion of one nucleotide at nucleotide position 688, causing a translational frameshift with a predicted alternate stop codon (p.E230Sfs*10). This alteration has been detected in individuals with gastrointestinal stromal tumor (GIST) (Wagner AJ et al. Mod. Pathol., 2013 Feb;26:289-94; Nannini M et al. J. Med. Genet. 2013 Oct;50(10):653-61). 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. - |
SDHA-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2024 | The SDHA c.688delG variant is predicted to result in a frameshift and premature protein termination (p.Glu230Serfs*10). This variant was reported in an individual with a gastrointestinal stromal tumor (Wagner et al. 2013. PubMed ID: 22955521) and an individual with mitochondrial cardiomyopathy (Murdock et al. 2021. PubMed ID: 34363016). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as either likely pathogenic or pathogenic by numerous labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/472291/). Frameshift variants in SDHA are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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