Submissions for variant NM_004168.4(SDHA):c.990del (p.Arg329_Tyr330insTer)

dbSNP: rs886041867

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000318650	SCV000330649	pathogenic	not provided	2016-07-06	criteria provided, single submitter	clinical testing	The Y330X variant in the SDHA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y330X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Y330X as a pathogenic variant.
Ambry Genetics	RCV003298335	SCV004001103	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The c.990delC pathogenic mutation, located in coding exon 8 of the SDHA gene, results from a deletion of one nucleotide at nucleotide position 990, causing a translational frameshift with a predicted alternate stop codon (p.Y330*). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325197	SCV004031254	pathogenic	Paragangliomas 5	2023-08-01	criteria provided, single submitter	clinical testing	The SDHA c.990del (p.Tyr330Ter) variant deletes one nucleotide to cause a frameshift of the protein coding sequence and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This alteration was identified in an individual with a paraganglioma (internal data). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Myriad Genetics, Inc.	RCV003325197	SCV004189810	pathogenic	Paragangliomas 5	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765582	SCV004590860	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr330*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 280711). For these reasons, this variant has been classified as Pathogenic.