Submissions for variant NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)

gnomAD frequency: 0.00025  dbSNP: rs142441643

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131808	SCV000186863	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-16	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000627791	SCV000288157	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-31	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000413945	SCV000490791	pathogenic	not provided	2022-05-12	criteria provided, single submitter	clinical testing	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)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000148026	SCV000677113	pathogenic	Paragangliomas 5	2017-11-09	criteria provided, single submitter	research
Counsyl	RCV000148026	SCV000677772	pathogenic	Paragangliomas 5	2015-10-27	criteria provided, single submitter	clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000148026	SCV000778378	pathogenic	Paragangliomas 5	2018-06-06	criteria provided, single submitter	clinical testing	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.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000148026	SCV000804427	pathogenic	Paragangliomas 5	2017-06-10	criteria provided, single submitter	provider interpretation	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722034	SCV000853211	pathogenic	Pilocytic astrocytoma	2017-08-24	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000413945	SCV000884500	pathogenic	not provided	2018-05-21	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002478402	SCV000893699	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-10-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089554	SCV001244791	pathogenic	Leigh syndrome	2020-01-06	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000413945	SCV001250478	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SDHA: PVS1, PP1:Strong, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001089554	SCV001370210	pathogenic	Leigh syndrome	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP4,PP5.
Genomics England Pilot Project, Genomics England	RCV000148026	SCV001760160	likely pathogenic	Paragangliomas 5		criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000413945	SCV002009952	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000413945	SCV002020042	pathogenic	not provided	2021-10-15	criteria provided, single submitter	clinical testing
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799624	SCV002026125	pathogenic	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000148026	SCV002044344	pathogenic	Paragangliomas 5	2021-11-29	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4
AiLife Diagnostics, AiLife Diagnostics	RCV000413945	SCV002502762	pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131808	SCV002527776	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-25	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000148026	SCV002556866	pathogenic	Paragangliomas 5	2022-11-07	criteria provided, single submitter	clinical testing	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).
MGZ Medical Genetics Center	RCV000148026	SCV002579899	pathogenic	Paragangliomas 5	2022-04-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000413945	SCV004024961	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330507	SCV004039536	pathogenic	Neurodegeneration with ataxia and late-onset optic atrophy	2023-08-15	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000148026	SCV004045363	pathogenic	Paragangliomas 5	2023-04-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335126	SCV004046374	pathogenic	SDHA-Related Disorders		criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003474779	SCV004200605	pathogenic	Dilated cardiomyopathy 1GG	2023-08-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000413945	SCV004220328	pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000413945	SCV004225835	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	PP1, PP4, PVS1
Section on Endocrinology and Genetics, National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development	RCV000170328	SCV000222637	likely pathogenic	Carney triad		no assertion criteria provided	clinical testing
OMIM	RCV000148026	SCV000246126	pathogenic	Paragangliomas 5	2023-10-17	no assertion criteria provided	literature only
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257553	SCV001434379	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000413945	SCV001743955	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000627791	SCV001749411	not provided	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5		no assertion provided	phenotyping only	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000413945	SCV001800132	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000413945	SCV001807733	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413945	SCV001967500	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413945	SCV001979558	pathogenic	not provided		no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV001762318	SCV002818549	pathogenic	Mitochondrial complex II deficiency, nuclear type 1	2022-08-04	no assertion criteria provided	clinical testing