ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.223C>T (p.Arg75Ter)

gnomAD frequency: 0.00003  dbSNP: rs781764920
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000684793 SCV000288131 pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2025-01-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg75*) 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 (rs781764920, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or pheochromocytoma (PMID: 23750034, 24694336). ClinVar contains an entry for this variant (Variation ID: 209127). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000481058 SCV000568513 pathogenic not provided 2024-04-29 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); This variant is associated with the following publications: (PMID: 32255556, 28500238, 27899191, 24694336, 27159395, 29978154, 28384794, 30877234, 33726816, 32570879, 23750034)
Ambry Genetics RCV000575496 SCV000664513 pathogenic Hereditary cancer-predisposing syndrome 2024-06-19 criteria provided, single submitter clinical testing The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 3 of the SDHA gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was reported in a woman with a paraganglioma diagnosed at age 20 (Welander J et al. J. Clin. Endocrinol. Metab., 2013 Aug;98:E1379-80) and in a male diagnosed with pheochromocytoma at 47 (Welander J et al. J Clin Endocrinol Metab, 2014 Jul;99:E1352-60). This mutation has also been identified in individuals with spindle cell breast cancer and pancreatic cancer (Sprissler R et al. Cancers (Basel), 2020 Jun;12; Cremin C et al. Cancer Med, 2020 06;9:4004-4013). 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.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000481058 SCV001449808 likely pathogenic not provided 2015-05-31 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Region Ostergotland RCV000191050 SCV001984994 pathogenic Paragangliomas 5 2021-04-19 criteria provided, single submitter clinical testing PVS1, PS4, PP5, BP5
Fulgent Genetics, Fulgent Genetics RCV002492875 SCV002801834 pathogenic Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy 2024-01-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV003474945 SCV004202390 pathogenic Dilated cardiomyopathy 1GG 2023-10-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481058 SCV004220296 pathogenic not provided 2023-01-31 criteria provided, single submitter clinical testing This nonsense variant causes the premature termination of SDHA protein synthesis. The frequency of this variant in the general population, 0.00065 (17/26134 chromosomes in Swedish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. However, in the published literature, this variant is reported as being associated with reduced penetrance of developing cancer (PMID: 29978154 (2018)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32570879 (2020)), pancreatic ductal adenocarcinoma (PDAC) (PMID: 32255556 (2020)), and hereditary paraganglioma-pheochromocytoma (PGL-PCC) (PMIDs: 30877234 (2019), 24694336 (2014), 23750034 (2013)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc. RCV000191050 SCV004933605 pathogenic Paragangliomas 5 2024-02-07 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.
OMIM RCV000191050 SCV000246128 pathogenic Paragangliomas 5 2013-08-01 no assertion criteria provided literature only

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