Submissions for variant NM_004168.4(SDHA):c.457-2_457del

dbSNP: rs878854632

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231881	SCV000288140	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-09-03	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 4 of the SDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 239672). This variant is also known as c.457-3_457-1delCAG. Disruption of this splice site has been observed in individuals with gastrointestinal stromal tumor (GIST) (PMID: 23109135, 23612575; Invitae). This variant is not present in population databases (gnomAD no frequency).
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799643	SCV002026138	pathogenic	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
Ambry Genetics	RCV002338730	SCV002637427	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	The c.457-2_457delAGC pathogenic mutation results from a deletion of AGC nucleotides between positions 457-2 and 457 and involves the canonical splice acceptor site before coding exon 5 of the SDHA gene. This mutation (also designated as c.457-3_457-1delCAG) has been reported as germline in individuals with gastrointestinal stromal tumors (GISTs) that demonstrated absent SDHB staining by IHC (Belinsky MG et al. Genes Chromosomes Cancer 2013 02;52(2):214-24; Pantaleo MA et al. Eur J Hum Genet 2014 Jan;22(1):32-9). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV004567735	SCV005056600	pathogenic	Dilated cardiomyopathy 1GG	2023-11-12	criteria provided, single submitter	clinical testing