Submissions for variant NM_004168.4(SDHA):c.64-2A>G

dbSNP: rs762456298

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036409	SCV001199770	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with mitochondrial complex II deficiency (PMID: 24781757). ClinVar contains an entry for this variant (Variation ID: 835516). Studies have shown that disruption of this splice site is associated with altered splicing resulting in altered splicing resulting in multiple RNA products (PMID: 24781757; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002363550	SCV002658937	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The c.64-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the SDHA gene. This variant was detected in the homozygous state in an individual with a multisystem mitochondrial disease; muscle biopsy and cultured fibroblasts from this individual showed reduced Complex II activity (Renkema GH et al. Eur J Hum Genet, 2015 Feb;23:202-9). This nucleotide position is highly conserved in available vertebrate species. 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 two abnormal transcripts (Renkema GH et al. Eur J Hum Genet, 2015 Feb;23:202-9; Ambry internal data). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528244	SCV001739647	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528244	SCV001951318	pathogenic	not provided		no assertion criteria provided	clinical testing