Submissions for variant NM_004168.4(SDHA):c.1534C>T (p.Arg512Ter)

gnomAD frequency: 0.00005  dbSNP: rs748089700

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411416	SCV000488005	likely pathogenic	Paragangliomas 5	2015-12-13	criteria provided, single submitter	clinical testing
Invitae	RCV000684799	SCV000553882	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg512*) 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 (rs748089700, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or gastrointestinal stromal tumor (PMID: 22955521, 25720320). ClinVar contains an entry for this variant (Variation ID: 371805). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000566844	SCV000664526	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	clinical testing	The p.R512* pathogenic mutation (also known as c.1534C>T), located in coding exon 11 of the SDHA gene, results from a C to T substitution at nucleotide position 1534. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in both the germline and in the tumor of an individual with an extra-adrenal paraganglioma and in the germline of an individual with a testis paraganglioma (Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 02;103(2):438-445). In another study, the mutation was carried by a 53-year-old female with metastatic retroperitoneal paraganglioma (Jha A et al. Front Oncol, 2019 Feb;9:53). This mutation has also been identified in several individuals with SDHA-deficient gastrointestinal stromal tumors (Wagner AJ et al. Mod Pathol, 2013 Feb;26:289-94; Jha A et al. Front Oncol, 2019 Feb;9:53). 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.
GeneDx	RCV000578965	SCV000680783	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with personal and family history consistent with pathogenic variants in this gene (Wagner 2013, Papathomas 2015, Maniam 2018, van der Tuin 2018, Ben Aim 2019); This variant is associated with the following publications: (PMID: 22955521, 25720320, 27011036, 28768491, 28546994, 24886695, 28748451, 23730622, 29978154, 31589614, 30877234, 31981491, 29177515, 32581362)
Illumina Laboratory Services, Illumina	RCV000411416	SCV001786670	pathogenic	Paragangliomas 5	2021-03-11	criteria provided, single submitter	clinical testing	The SDHA c.1534C>T (p.Arg512Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg512Ter variant has been reported in two studies in which it was identified as a germline variant in at least two affected individuals including one individual with a paraganglioma and one individual with a gastrointestinal stromal tumor (Wagner et al. 2013; Papathomas et al. 2015). The p.Arg512Ter variant is reported at a frequency of 0.000078 in the European (non-Finnish) population from of the Genome Aggregation Database. This allele frequency is high but is may be consistent with reduced penetrance. Based on the available evidence and application of the ACMG criteria, the p.Arg512Ter variant is classified as pathogenic for hereditary pheochromocytoma-paraganglioma syndrome.
CeGaT Center for Human Genetics Tuebingen	RCV000578965	SCV002497299	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	SDHA: PVS1
AiLife Diagnostics, AiLife Diagnostics	RCV000578965	SCV002502821	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566844	SCV002527721	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002502437	SCV002811147	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-09-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411416	SCV004018616	pathogenic	Paragangliomas 5	2023-04-21	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.
Baylor Genetics	RCV003475994	SCV004200590	pathogenic	Dilated cardiomyopathy 1GG	2024-03-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000578965	SCV004225946	likely pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	PP4, PVS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017601	SCV004848632	pathogenic	Hereditary pheochromocytoma-paraganglioma	2022-06-30	criteria provided, single submitter	clinical testing	The p.Arg512X variant in SDHA has been reported in 5 individuals with SDHA-related tumors (paragangliomas, pheochromocytomas, GISTs) and segregated with disease in 2 affected individuals from 2 families (Wagner 2013 PMID: 22955521, Papathomas 2015 PMID: 25720320, van der tuin 2018 PMID: 29177515, Ben Aim 2019 PMID: 30877234, Whitworth 2021 PMID: 33854214). It has also been identified in 0.009% (6/68038) of European chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 371805). This nonsense variant leads to a premature termination codon at position 512, which is predicted to lead to a truncated or absent protein. Loss of function of the SDHA gene is an established disease mechanism in autosomal dominant Hereditary paraganglioma-pheochromocytoma syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Hereditary paraganglioma-pheochromocytoma. ACMG/AMP Criteria applied: PS4, PVS1, PM2_P.
Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe	RCV002285327	SCV002573785	pathogenic	Opsoclonus-myoclonus syndrome		no assertion criteria provided	clinical testing