Submissions for variant NM_004168.4(SDHA):c.151-2A>G

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003086856	SCV003483076	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-06-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 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 benign sporadic primary hyperparathyroidism (PMID: 35586626). ClinVar contains an entry for this variant (Variation ID: 2168252). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003455712	SCV004189651	likely pathogenic	Paragangliomas 5	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Ambry Genetics	RCV004073222	SCV005021371	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The c.151-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 3 in the SDHA gene. 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 may 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). Another alteration impacting the same acceptor site (c.151-1G>C) has been shown to have a similar impact on splicing and observed in at least one individual with a personal and/or family history that is consistent with SDHA-related disease (Ambry internal data). 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.
GeneDx	RCV004725525	SCV005332772	likely pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Observed in an individual with hyperparathyroidism (PMID: 35586626); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35586626)