Submissions for variant NM_004168.4(SDHA):c.1909-1G>A

dbSNP: rs1159597886

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574361	SCV000674960	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The c.1909-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 15 of the SDHA gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been observed in individuals with a personal and/or family history that is consistent with SDHA-related disease (Ambry internal data). 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 alteration occurs at the 3' terminus of the SDHA gene, is not expected to undergo nonsense-mediated mRNA decay, and impacts 4% of the protein structure. Internal structural analysis has determined disruption of this region to impact protein function (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203781	SCV001374958	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 of the SDHA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with gastrointestinal stromal tumors (PMID: 28546994; Invitae). ClinVar contains an entry for this variant (Variation ID: 486365). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). 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.	RCV004024569	SCV004930736	likely pathogenic	Paragangliomas 5	2023-12-12	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.