Submissions for variant NM_004168.4(SDHA):c.1885dup (p.Tyr629fs)

gnomAD frequency: 0.00001  dbSNP: rs750865703

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000537063	SCV000651416	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2022-02-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr629Leufs*14) in the SDHA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the SDHA protein. This variant is present in population databases (rs750865703, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with paraganglioma and pheochromocytoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 472365). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV001013539	SCV001174138	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	The c.1885dupT pathogenic mutation, located in coding exon 14 of the SDHA gene, results from a duplication of T at nucleotide position 1885, causing a translational frameshift with a predicted alternate stop codon (p.Y629Lfs*14). This alteration occurs at the 3' terminus of theSDHA gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 36 amino acids of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). In addition, this alteration has been detected in multiple individuals with a paraganglioma (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001555544	SCV001776982	likely pathogenic	not provided	2020-11-11	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation and affect the functionally important C-terminal region, as the last 36 amino acids are lost and replaced with 13 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Kim 2012, Stenson 2014); Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV003451192	SCV004189646	likely pathogenic	Paragangliomas 5	2023-11-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003476311	SCV004200609	likely pathogenic	Dilated cardiomyopathy 1GG	2023-07-31	criteria provided, single submitter	clinical testing