rs142441643
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting
The NM_004168.4(SDHA):c.91C>T(p.Arg31Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00042 ( 0 hom. )
Consequence
SDHA
NM_004168.4 stop_gained
NM_004168.4 stop_gained
Scores
1
3
3
Clinical Significance
Conservation
PhyloP100: 0.680
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 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 150 pathogenic variants in the truncated region.
PP5
Variant 5-223509-C-T is Pathogenic according to our data. Variant chr5-223509-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-223509-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-223509-C-T is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00042 (614/1461298) while in subpopulation NFE AF= 0.00054 (600/1111516). AF 95% confidence interval is 0.000504. There are 0 homozygotes in gnomad4_exome. There are 320 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SDHA | NM_004168.4 | c.91C>T | p.Arg31Ter | stop_gained | 2/15 | ENST00000264932.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SDHA | ENST00000264932.11 | c.91C>T | p.Arg31Ter | stop_gained | 2/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes 0.000243 AC: 37AN: 152202Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
37
AN:
152202
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000195 AC: 49AN: 251180Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135742
GnomAD3 exomes
AF:
AC:
49
AN:
251180
Hom.:
AF XY:
AC XY:
31
AN XY:
135742
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000420 AC: 614AN: 1461298Hom.: 0 Cov.: 30 AF XY: 0.000440 AC XY: 320AN XY: 727008
GnomAD4 exome
AF:
AC:
614
AN:
1461298
Hom.:
Cov.:
30
AF XY:
AC XY:
320
AN XY:
727008
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000243 AC: 37AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19AN XY: 74356
GnomAD4 genome
AF:
AC:
37
AN:
152202
Hom.:
Cov.:
33
AF XY:
AC XY:
19
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
2
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
20
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:38Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:14
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 15, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 23, 2022 | This nonsense variant causes the premature termination of SDHA protein synthesis. In the published literature, the variant has been reported in patients with paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors (PMIDs: 26173966 (2016), 26490314 (2016), 25494863 (2015), 26259135 (2015), 23666964 (2013), 22955521 (2013), 23174939 (2013)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 28, 2023 | PP1, PP4, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 21, 2018 | The SDHA c.91C>T; p.Arg31Ter variant (rs142441643) is reported in the literature associated with disease in multiple patients. Genetic testing of a gastrointestinal stromal tumor (GIST) in a young adult patient identified the p.Arg31Ter variant in trans from another pathogenic variant (p.Arg589Trp); subsequent testing revealed that the p.Arg31Ter variant was germline whereas the p.Arg589Trp variant was detected only in the tumor (Pantaleo 2011). Another study of paragangliomas (PGL) and pheochromocytomas identified the p.Arg31Ter variant in four tumors (patients were heterozygous for germline p.Arg31Ter, whereas tumors showed loss-of-heterozygosity); however, the same variant was also identified in 0.3% of healthy controls (Korpershoek 2011). A number of other studies have reported the p.Arg31Ter variant in both PGL and non-PGL tumors, often with evidence of p.Arg31Ter as a germline variant in affected patients (Boikos 2016, Denes 2015, Else 2017, Lussey-Lepoutre 2016, Niemeijer 2015, Oudijk 2013, Rattenberry 2013, Wagner 2013). Finally, p.Arg31Ter was also identified in trans from a germline p.Cys189Gly variant in a patient with multisystem mitochondrial disease (Renkema 2015). The p.Arg31Ter variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 142601). It is found in the general population databases with an overall allele frequency of 0.02% (58/276948 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. However, pathogenic heterozygous SDHA variants have incomplete penetrance (Casey 2017) and the individual risk has yet to be determined. REFERENCES Boikos SA et al. Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet. 2016 Apr;24(4):569-73. Casey RT et al. SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity. Mol Genet Genomic Med. 2017 Mar 2;5(3):237-250. Denes J et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015 Mar;100(3):E531-41. Else T et al. Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. Eur J Endocrinol. 2017 Nov;177(5):439-444. Korpershoek E et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011 Sep;96(9):E1472-6. Lussey-Lepoutre C et al. In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma. Clin Cancer Res. 2016 Mar 1;22(5):1120-9. Niemeijer ND et al. Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. J Clin Endocrinol Metab. 2015 Oct;100(10):E1386-93. Oudijk L et al. SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors. Mod Pathol. 2013 Mar;26(3):456-63. Pantaleo MA et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst. 2011 Jun 22;103(12):983-7. Rattenberry E et al. A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013 Jul;98(7):E1248-56. Renkema GH et al. SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. Eur J Hum Genet. 2015 Feb;23(2):202-9. Wagner AJ et al. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013 Feb;26(2):289-94. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2022 | Observed with a second SDHA variant on the opposite allele (in trans) in an individual with Leigh syndrome (Renkema 2015); 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; Published functional studies demonstrate loss of protein expression (Dubard Gault 2018); This variant is associated with the following publications: (PMID: 31368675, 30854332, 25394176, 27171833, 23252569, 27604842, 28546994, 22974104, 30877234, 25525159, 24886695, 23612575, 25494863, 26259135, 23109135, 21505157, 23666964, 21752896, 27895137, 28819017, 22955521, 23174939, 30068732, 29978187, 26173966, 29625052, 26689913, 29177515, 28500238, 31169996, 29978154, 32581362, 31827275, 34308366, 31589614, 33372952, 33077847, 33960148, 33674644, 24781757) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | SDHA: PVS1, PP1:Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 09, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Paragangliomas 5 Pathogenic:10
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Nov 09, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 24, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 29, 2021 | _x000D_ Criteria applied: PVS1, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 27, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Jun 10, 2017 | This 6 year old male with global developmental delays (at-risk for mild intellectual disability), ADHD, disruptive behavior, and mild overgrowth was found to carry a paternally inherited nonsense variant in the SDHA gene. The R31X pathogenic variant in the SDHA gene has been reported previously in the heterozygous state in association with hereditary paraganglioma-pheochromocytoma syndrome (Korpershoek et al., 2011; Rattenberry et al., 2013; Batsis et al., 2016) and in individuals with gastrointestinal stromal tumors (Pantaleo et al., 2011; Wagner et al., 2013; Oudijk et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The patient does not yet show any signs of hereditary paraganglioma-pheochromocytoma syndrome. His father has not yet been formally evaluated, but he reports a history of hypertension. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 07, 2022 | The SDHA c.91C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PS3) The SDHA c.91C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 31 (PVS1). This variant has been reported in multiple individuals with gastrointestinal stromal tumors (GIST), paragangliomas (PGL), pheochromocytomas (PCC), Carney triad (PMID: 26173966), as well as non-PGL tumors (PMID: 21505157, 22955521, 23174939, 21752896, 23666964, 25494863, 26259135) (PS4_Moderate). Well-established functional studies show a deleterious effect of this variant (PMID:24781757) (PS3). The variant has been reported in dbSNP (rs142441643) and has been reported in population databases (gnomAD 37/152202, 0 homozygotes). The variant has been reported in the HGMD database as disease causing (CM114717) and as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 142601). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pediatrics, Memorial Sloan Kettering Cancer Center | Jun 06, 2018 | This mutation was observed in 9 patients in our cancer study. Additional supporting evidence for this mutation contributing to the specific cancers manifested by patients in our cohort, were in the settings of GIST and neuroblastoma. For patients with other cancer types in our cohort, this alteration is suggestive of an independent risk factor for cancers than experienced by the patients. - |
Leigh syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP4,PP5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jan 06, 2020 | A heterozygous nonsense variant, NM_004168.2(SDHA):c.91C>T, has been identified in exon 2 of 15 of the SDHA gene. The variant is predicted to result in a premature stop codon at position 31 of the protein (NP_004159.2(SDHA):p.(Arg31*)), likely causing nonsense-mediated decay. This variant is predicted to result in loss of protein function either through truncation (including FAD-dependent oxidoreductase 2 domain and fumerate reductase/succinate dehydrogenase flavoprotein-like, C-terminal domain) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.0209%. The variant has been previously described as pathogenic in a compound heterozygous state in one patient with Leighsyndrome (Renkema GH. et al., (2015)). Functional analysis demonstrated a partial reduction in protein and almost complete loss of complex II activity (Renkema GH. et al., (2015)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 25, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2022 | The p.R31* pathogenic mutation (also known as c.91C>T), located in coding exon 2 of the SDHA gene, results from a C to T substitution at nucleotide position 91. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported in multiple individuals diagnosed with isolated paraganglioma (Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; Bahougne T et al. Endocr. Relat. Cancer. 2017 Feb;24:L7-L11; Lussey-Lepoutre C et al. Clin. Cancer Res. 2016 Mar;22:1120-9). This mutation was also detected in 2/692 (0.3%) Dutch controls, which suggests a low penetrance of paragangliomas in individuals with this mutation (Korpershoek E et al. J. Clin. Endocrinol. Metab. 2011 Sep;96:E1472-6). This alteration has also been reported in individuals with gastrointestinal stromal tumors and pheochromocytomas, an individual with adrenocortical carcinoma, and an individual with SDHA-deficient renal cell carcinoma (Pantaleo MA et al. J. Natl. Cancer Inst. 2011 Jun;103:983-7; Wagner AJ et al. Mod. Pathol. 2013 Feb;26:289-94; Oudijk L et al. Mod. Pathol. 2013 Mar;26:456-63; Else T et al. Eur. J. Endocrinol. 2017 Nov;177:439-444; McEvoy CR et al. NPJ Precis Oncol. 2018 Mar;2:9; Dubard Gault M et al. Cold Spring Harb Mol Case Stud. 2018 08;4:(4); Tufton N et al. Endocr. Relat. Cancer. 2017 07;24:L43-L49). 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. - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg31*) 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 present in population databases (rs142441643, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with gastrointestinal stromal tumors (GIST), paragangliomas (PGL), pheochromocytomas (PCC), Carney triad and autosomal-recessive complex II deficiency (PMID: 21505157, 21752896, 22955521, 23174939, 23666964, 24781757, 25494863, 26173966, 26259135). ClinVar contains an entry for this variant (Variation ID: 142601). For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 04-20-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Aug 04, 2022 | - - |
Carney triad Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Section on Endocrinology and Genetics, National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development | - | - - |
Pilocytic astrocytoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 24, 2017 | This is a nonsense alteration in which a C is replaced by a T at coding nucleotide 91 and is predicted to change an Arginine to a premature stop codon at amino acid codon 31. Classification criteria: PVS1, PS1, PP5. - |
Rhabdomyosarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 01, 2020 | - - |
Gastrointestinal stromal tumor Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | “Giorgio Prodi” Cancer Research Center, University of Bologna | Oct 01, 2021 | - - |
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
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 02, 2021 | - - |
Dilated cardiomyopathy 1GG Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 24, 2024 | - - |
Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2023 | Variant summary: SDHA c.91C>T (p.Arg31X) 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. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.0002 in 251180 control chromosomes (gnomAD). c.91C>T has been reported in the literature in multiple individuals affected with pheochromocytomas and paragangliomas, SSDH-deficient gastrointestinal stromal tumors and significant ataxia, with progressive cerebellar atrophy (examples: Korpershoek_ 2011, Panteleo_ 2022, Sturrock_ 2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35059314, 21752896, 33960148). Twenty two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=20)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
SDHA-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This nonsense variant found in exon 2 of 15 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been reported in multiple individuals with gastrointestinal stromal tumors (GIST), paragangliomas (PGL), pheochromocytomas (PCC), Carney triad (PMID: 26173966), and non-PGL tumors (PMID: 21505157, 22955521, 23174939, 21752896, 23666964, 25494863, 26259135). This variant has also been reported as a compound heterozygous change in an individual diagnosed with autosomal-recessive complex II deficiency (PMID: 24781757). Functional studies showed that the presence of this variant caused reduced expression of SDHA protein and mitochondrial complex II enzyme activity (PMID: 24781757). Loss-of-function variants are an established mechanism of disease in SDHA-related disorders (HGMD, ClinVar database). The c.91C>T (p.Arg31Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.021% (59/282590) and thus is presumed to be rare. Based on the available evidence, the c.91C>T (p.Arg31Ter) variant is classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at