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

gnomAD frequency: 0.00007  dbSNP: rs34599281

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231407	SCV000287762	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2025-01-23	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	2024-08-01	criteria provided, single submitter	clinical testing	Observed in individuals with pheochromocytoma/paraganglioma, breast cancer, or other cancer (PMID: 25694510, 28873162, 30086788, 34271781, 34906457); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25694510, 28873162, 30086788, 29510530, 28819017, 34426522, 34271781, 34326862, 34906457, 38473309, 30476936)
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	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000626075	SCV005056626	uncertain significance	Gastrointestinal stromal tumor	2024-03-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001563210	SCV005624021	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	The SDHB c.178A>G (p.Thr60Ala) variant has been reported in the published literature in individuals with pheochromocytomas or paragangliomas (PMID: 34906457 (2022)), thyroid cancer (PMIDs: 29684080 (2018), 25694510 (2015)), breast cancer (PMID: 34326862 (2021)), and unspecified advanced cancer (28873162 (2017)). The frequency of this variant in the general population, 0.00011 (13/113648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001294008	SCV005689294	uncertain significance	Paragangliomas 4	2024-07-08	criteria provided, single submitter	clinical testing	The SDHB c.178A>G (p.Thr60Ala) missense change has a maximum frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/ ). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary paraganglioma-pheochromocytoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004732805	SCV005350897	uncertain significance	SDHB-related disorder	2024-03-25	no assertion criteria provided	clinical testing	The SDHB c.178A>G variant is predicted to result in the amino acid substitution p.Thr60Ala. This variant was reported in individuals with thyroid cancer, breast cancer, or pheochromocytomas/paragangliomas (Ni et al. 2015. PubMed ID: 25694510; eTable in Supplement 2, Mandelker et al. 2017. PubMed ID: 28873162; Penkert et al. 2018. PubMed ID: 30086788; Table S2, Garrett et al. 2022. PubMed ID: 34906457). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239423/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.