Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Rady Children's Institute for Genomic Medicine, |
RCV000853252 | SCV000996073 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1 | 2017-09-21 | criteria provided, single submitter | clinical testing | This variant impacts the splice site at the start of exon 14. The nucleotide residue is highly conserved at this position and is predicted to be a loss-of-function variant that negatively impacts SDHA protein function. There is one report of the variant as pathogenic in an individual with a germline heterozygous c.1796-1G>T variant and a SDHA deficiency-linked gastrointestinal stromal tumor (GIST) (PMID: 23282968). There is one report of this variant in the public reference database gnomAD, thus it is presumed rare. Based on the available evidence, the variant is classified as pathogenic. |
Ambry Genetics | RCV001013115 | SCV001173657 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-10-23 | criteria provided, single submitter | clinical testing | The c.1795-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 14 of the SDHA gene. This alteration has been reported as a germline mutation in an individual with a GIST (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40). This alteration has been reported in conjunction with SDHA c.480T>G (p.F160L) in an patient with mitochondrial complex II deficiency (De La Vega FM et al. Genome Med, 2021 Oct;13:153). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Labcorp Genetics |
RCV001379066 | SCV001576795 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2021-01-18 | criteria provided, single submitter | clinical testing | 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. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with gastrointestinal stromal tumor (PMID: 23282968). ClinVar contains an entry for this variant (Variation ID: 691997). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change affects an acceptor splice site in intron 13 of the SDHA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |