ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.178A>G (p.Thr60Ala)

gnomAD frequency: 0.00007  dbSNP: rs34599281
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231407 SCV000287762 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 60 of the SDHB protein (p.Thr60Ala). This variant is present in population databases (rs34599281, gnomAD 0.01%). This missense change has been observed in individual(s) with adenocortical carcinoma and/or thyroid cancer (PMID: 25694510, 28819017). ClinVar contains an entry for this variant (Variation ID: 239423). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHB protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000568901 SCV000664615 likely benign Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000626075 SCV000746699 uncertain significance Gastrointestinal stromal tumor 2017-12-18 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001095844 SCV001252021 benign Hereditary pheochromocytoma-paraganglioma 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina RCV001100086 SCV001256587 benign Carney-Stratakis syndrome 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Baylor Genetics RCV001294008 SCV001482759 uncertain significance Paragangliomas 4 2019-10-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001563210 SCV001786112 uncertain significance not provided 2023-04-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pheochromocytomas or paragangliomas, and breast or other cancers (Ni et al., 2015; Mandelker et al., 2017; Penkert et al., 2018; Duzkale et al., 2021; Garrett et al., 2022); This variant is associated with the following publications: (PMID: 25694510, 28873162, 30086788, 29510530, 28819017, 34426522, 34271781, 34906457)
Sema4, Sema4 RCV000568901 SCV002527062 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-26 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465589 SCV002760645 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing

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