Submissions for variant NM_004168.4(SDHA):c.775del (p.Tyr259fs)

dbSNP: rs1553998606

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572546	SCV000675020	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	The c.775delT pathogenic mutation, located in coding exon 7 of the SDHA gene, results from a deletion of one nucleotide at nucleotide position 775, causing a translational frameshift with a predicted alternate stop codon (p.Y259Tfs*21). 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.
Illumina Laboratory Services, Illumina	RCV000778763	SCV000915130	uncertain significance	SDHA-related disorder	2018-12-12	criteria provided, single submitter	clinical testing	The SDHA c.775delT (p.Tyr259ThrfsTer21) variant is a stop-gained variant that is predicted to result in a premature termination. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for SDHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810235	SCV000950428	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr259Thrfs*21) 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: 486395). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004024570	SCV004930873	pathogenic	Paragangliomas 5	2024-01-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.