Submissions for variant NM_003001.5(SDHC):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs755235380

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791400	SCV000546039	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 3	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs755235380, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with clinical features of SDHC-related conditions (PMID: 11062460, 16249420, 19454582, 22351710, 22517554, 23282968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407060). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492170	SCV000581217	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-21	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the SDHC gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This mutation has previously been reported in multiple individuals diagnosed with paragangliomas (Schiavi F et al. JAMA. 2005 Oct;294:2057-63; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Am J Surg Pathol 2013 Feb;37(2):234-40; Niemann S et al. Nat Genet 2000 Nov;26(3):268-70). The mutation was also detected in an individual whose GIST tumor showed a loss of SDHB expression and intact SDHA expression on IHC (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000467345	SCV000782281	pathogenic	Paragangliomas 3	2016-11-01	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000467345	SCV001434947	pathogenic	Paragangliomas 3	2018-10-12	criteria provided, single submitter	clinical testing	This rare c.1A>G (p.Met1?) variant (seen once in gnomAD) in the SDHC gene is predicted to result in a start codon loss of the major biological transcripts. The variant has been observed in multiple unrelated individuals paraganglioma/pheochromocytoma (PMID 16249420, 19351833, 19454582). Predicted start codon loss with different nucleotide changes in this gene has been also observed in other individuals with paraganglioma (PMID : 19351833) . Therefore, this c.1A>G (p.Met1?) variant variant is considered as pathogenic.
New York Genome Center	RCV000467345	SCV001622967	pathogenic	Paragangliomas 3	2020-07-17	criteria provided, single submitter	clinical testing	The variant c.1A>G affects the initiator methionine of the SDHC mRNA. This variant is present in population databases (gnomAD v30.001%) and has been reported in the literature in 3 individuals affected with paraganglioma/pheochromocytoma and gastrointestinal stromal tumors [PMID: 23282968; PMID: 22517554; PMID: 19454582], and in a family with Paraganglioma Syndrome [PMID: 16249420]. Two different variants (c.2T>A and c.3G>A) that disrupt the same methionine initiator have been reported in patients and families affected with head and neck paragangliomas [PMID: 19351833], paragangliomas [PMID: 11062460], and renal cell carcinoma [PMID: 22351710], indicating that this methionine initiator of SDHC may be critical for protein function. Based on the available evidence, this variant has been classified as Pathogenic.
GeneDx	RCV001559453	SCV001781683	pathogenic	not provided	2025-02-11	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); This variant is associated with the following publications: (PMID: 19454582, 22517557, 27011036, 23282968, 19351833, 28748451, 16249420, 31589614, 33087929, 34558728, 24096523, 31447099, 22517554, 22351710, 11062460, 34750850, 30201732, 30877234)
Myriad Genetics, Inc.	RCV000467345	SCV004018724	pathogenic	Paragangliomas 3	2024-02-15	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: 30201732, 30877234, 16249420, 11062460, 25720320].