ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1432_1432+1del

gnomAD frequency: 0.00001  dbSNP: rs878854627
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228421 SCV000288110 pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2024-01-05 criteria provided, single submitter clinical testing This variant results in the deletion of part of exon 10 (c.1432_1432+1del) of the SDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with breast cancer, paraganglioma-pheochromocytoma syndrome, and/or renal cancer (PMID: 29177515, 30877234, 32782288, 34750850; Invitae). ClinVar contains an entry for this variant (Variation ID: 239647). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000567345 SCV000664480 pathogenic Hereditary cancer-predisposing syndrome 2021-11-29 criteria provided, single submitter clinical testing The c.1432_1432+1delGG pathogenic mutation spans the coding exon 10/intron 10 boundary of the SDHA gene and results from the deletion of 2 nucleotides at nucleotide positions c.1432 and c.1432+1. The deleted region includes the last nucleotide and canonical donor site, which is highly conserved in available vertebrate species. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHA-related disease (Ambry internal data; Bausch B et al. JAMA Oncol 2017 Sep;3(9):1204-1212; van der Tuin K et al. J Clin Endocrinol Metab 2018 02;103(2):438-445). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001253762 SCV001429631 pathogenic Pheochromocytoma; Paraganglioma 2020-07-10 criteria provided, single submitter clinical testing This variant has been observed in a male proband with phaeochromocytoma and lung nodule. The variant has previously been reported in the literature, including in a male with glomus jugulare tumour (PMID: 29177515); a male with retroperitoneal paraganglioma (PMID 28384794); a male with gallbladder paraganglioma, pancreatic neuroendocrine tumour and metastatic prostate cancer (PMID: 32534711); and a female with thoracic paraganglioma (PMCID: PMC7209502) (PS4_moderate). The variant is absent from population database gnomAD (PM2_supporting) and is predicted to result in loss of protein function (PVS1_very_strong). Data included in classification: Prevalence in affected versus controls GT-AG 1,2 splice site variant predicted to result in loss of protein function Data not included in classification: Functional data
Fulgent Genetics, Fulgent Genetics RCV002500781 SCV002812187 likely pathogenic Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy 2022-01-11 criteria provided, single submitter clinical testing
GeneDx RCV002508205 SCV002818021 pathogenic not provided 2022-12-28 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele 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: 24781757, 22974104, 31263571, 16199547, 30877234, 29177515, 26556299, 34750850, 32782288, 35053433)
Baylor Genetics RCV003475069 SCV004202368 pathogenic Dilated cardiomyopathy 1GG 2023-10-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003492005 SCV004241806 pathogenic Neurodegeneration with ataxia and late-onset optic atrophy 2023-12-04 criteria provided, single submitter clinical testing Variant summary: SDHA c.1432_1432+1delGG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251166 control chromosomes (gnomAD). c.1432_1432+1delGG has been reported in the literature in individuals affected with paraganglioma or cancers including renal cancer (van der Tuin_2018, Ben Aim_2019, Hartman_2020, Parisien-La Salle_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29177515, 30877234, 34750850, 32782288). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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