rs1553998199
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004168.4(SDHA):c.688del(p.Glu230SerfsTer10) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G229G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004168.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.688del | p.Glu230SerfsTer10 | frameshift_variant | 6/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.688del | p.Glu230SerfsTer10 | frameshift_variant | 6/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461562Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727112
GnomAD4 genome ? Cov.: 33
ClinVar
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 | Invitae | 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 | May 23, 2023 | 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: 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at