rs1553998199
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000264932.11(SDHA):βc.688delβ(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 (β β ). 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
ENST00000264932.11 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.688del | p.Glu230SerfsTer10 | 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.688del | p.Glu230SerfsTer10 | frameshift_variant | 6/15 | 1 | NM_004168.4 | ENSP00000264932 | 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 | Myriad Genetics, Inc. | Feb 07, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
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. - |
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at