ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.1A>T (p.Met1Leu) (rs104894307)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485004 SCV000572141 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing This variant alters the initiator Methionine codon, and the resultant protein would be described as “p.Met1?” to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. While SDHD c.1A>T has not, to our knowledge, been reported in the literature as pathogenic or benign, several other nucleotide changes also resulting in p.Met1? have been reported in individuals affected with multiple and/or early-onset paragangliomas, with both sporadic and familial presentations (Riemann 2003, Neumayer 2007, Burnichon 2009, Zha 2011, Wang 2012, Piccini 2012), Based on the current evidence, we consider SDHD c.1A>T to be pathogenic.
Ambry Genetics RCV000492287 SCV000581226 pathogenic Hereditary cancer-predisposing syndrome 2012-06-19 criteria provided, single submitter clinical testing
Invitae RCV000813371 SCV000953729 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2018-09-28 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHD mRNA. An alternate in-frame methionine downstream of the initiator codon is located at codon 91, which could potentially rescue translational initiation. This variant is present in population databases (rs104894307, ExAC 0.001%). Disruption of the initiator codon has been observed in individuals and families with head and neck paragangliomas (HNPGLs) or non-HNPGLs, and were shown to segregate with disease in the affected families (PMID: 17406045, 12782822, 11391796, 17576205, 21945342). ClinVar contains an entry for this variant (Variation ID: 422629). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the loss of ~60% of the SDHD protein, including the signal peptide domain required for entering the mitochondrial membrane (PMID: 12612654, 15066320). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.