Submissions for variant NM_003000.3(SDHB):c.3G>A (p.Met1Ile)

dbSNP: rs1131691061

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492186	SCV000581214	pathogenic	Hereditary cancer-predisposing syndrome	2017-08-24	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.3G>A), located in coding exon 1 of the SDHB gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This alteration has been detected in multiple individuals with paraganglioma and/or pheochromocytoma (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6; Piccini V et al. Endocr. Relat. Cancer 2012 Apr;19(2):149-55; Sjursen W et al. Fam. Cancer 2013 Sep;12(3):529-35; Papathomas TG et al. Eur. J. Endocrinol. 2014 Jan;170:1-12). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379744	SCV001577603	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2021-07-19	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SDHB mRNA. The next in-frame methionine is located at codon 58. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individuals with paragangliomas, pheochromocytomas and renal cell carcinomas (PMID: 19351833, 22241717, 23407919, 23512077, 24096523, 25047027, 27279923, 28490599, 29951630). ClinVar contains an entry for this variant (Variation ID: 428932). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002289679	SCV002580781	pathogenic	Pheochromocytoma	2022-02-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV004003475	SCV004362289	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-05-08	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon (methionine at codon 1) of the SDHB gene. This variant is expected to disrupt the expression of the full-length SDHB protein. The next in-frame methionine occurs at codon 58, but it is not known if a functional SDHB protein product can be produced using p.Met58 as an alternative translation start site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19351833, 22241717, 23407919, 27279923, 27279923, 32688340). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004003475	SCV004830194	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-06-08	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon (methionine at codon 1) of the SDHB gene. This variant is expected to disrupt the expression of the full-length SDHB protein. The next in-frame methionine occurs at codon 58, but it is not known if a functional SDHB protein product can be produced using p.Met58 as an alternative translation start site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19351833, 22241717, 23407919, 27279923, 27279923, 32688340). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV000550393	SCV004933764	pathogenic	Paragangliomas 4	2023-12-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:28503760, 32688340, 24096523, 28374168].
GeneDx	RCV004701556	SCV005202015	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	Initiation codon variant 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 multiple individuals with a personal and/or family history of SDHB-related tumors in published literature (Neumann et al., 2009; Piccini et al., 2012; Sjursen et al., 2013; Bayley et al., 2020; Main et al., 2020); This variant is associated with the following publications: (PMID: 19351833, 23407919, 31492822, 32688340, 24096523, 22241717, 27279923)
CeGaT Center for Human Genetics Tuebingen	RCV004701556	SCV005434023	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	SDHB: PS4, PM2, PS1:Moderate, PVS1:Moderate
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV004003475	SCV005689611	pathogenic	Hereditary pheochromocytoma-paraganglioma	2025-01-24	criteria provided, single submitter	clinical testing	The following ACMG criteria have been used in classification: PM2_SUP; PVS1_MOD; PS4; PS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004701556	SCV005873486	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing