ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1468G>T (p.Glu490Ter)

dbSNP: rs1554000360
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000538564 SCV000651336 pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2025-01-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu490*) 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 tumors (PMID: 28546994). ClinVar contains an entry for this variant (Variation ID: 472288). For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center RCV001523818 SCV001478179 pathogenic Paragangliomas 5 2020-12-15 criteria provided, single submitter research
Sema4, Sema4 RCV002256388 SCV002527716 likely pathogenic Hereditary cancer-predisposing syndrome 2021-06-21 criteria provided, single submitter curation
Ambry Genetics RCV002256388 SCV002698831 pathogenic Hereditary cancer-predisposing syndrome 2024-01-17 criteria provided, single submitter clinical testing The p.E490* pathogenic mutation (also known as c.1468G>T), located in coding exon 11 of the SDHA gene, results from a G to T substitution at nucleotide position 1468. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This alteration has been reported in an individual with a personal history of a gastrointestinal stromal tumor diagnosed at age 32 (Casey RT et al. Mol Genet Genomic Med, 2017 May;5:237-250). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 RCV003317276 SCV004021339 likely pathogenic not provided 2023-01-09 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 a patient with metastatic gastrointestinal stromal tumor (Casey et al., 2017); This variant is associated with the following publications: (PMID: 24781757, 22974104, 28873162, 28546994, 34308366)
Baylor Genetics RCV003476302 SCV004200668 pathogenic Dilated cardiomyopathy 1GG 2024-02-23 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001523818 SCV004933792 pathogenic Paragangliomas 5 2024-02-08 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.

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