Submissions for variant NM_004168.4(SDHA):c.1663+3G>C

gnomAD frequency: 0.00004  dbSNP: rs751904543

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700223	SCV000828971	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the SDHA gene. It does not directly change the encoded amino acid sequence of the SDHA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs751904543, gnomAD 0.006%). This variant has been observed in individuals with gastrointestinal stromal tumor and paraganglioma (PMID: 23060355, 30877234; Invitae). ClinVar contains an entry for this variant (Variation ID: 577461). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799703	SCV002026144	uncertain significance	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
Ambry Genetics	RCV002397443	SCV002708395	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	The c.1663+3G>C intronic variant results from a G to C substitution 3 nucleotides after coding exon 12 in the SDHA gene. This alteration has been detected in two individuals with a paraganglioma; tumor analyses showed the presence of a somatic pathogenic SDHA mutation and/or loss of SDHA and SDHB by immunohistochemistry (Ben Aim L et al. J Med Genet, 2019 08;56:513-520). In addition, this variant was identified in a gastrointestinal stromal tumor with negative SDHA immunostaining, as well as non-neoplastic tissue of the same patient (Dwight T et al. Am J Surg Pathol, 2013 Feb;37:226-33). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing (Ben Aim L et al. J Med Genet, 2019 08;56:513-520; Ambry internal data). Another alteration impacting the same donor site (c.1663+1G>T) has been shown to have a similar impact on splicing and has also been reported in an individual with a gastrointestinal stromal tumor (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV004026507	SCV004933582	likely pathogenic	Paragangliomas 5	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30877234, 35059314]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 30877234].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696982	SCV005198190	likely pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735755	SCV005345922	likely pathogenic	SDHA-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The SDHA c.1663+3G>C variant is predicted to interfere with splicing. This variant has been reported in individuals with gastrointestinal stromal tumors and individuals with paragangliomas (Dwight et al. 2013. PubMed ID: 23060355; Pantaleo et al. 2022. PubMed ID: 35059314; Ben Aim et al. 2019. PubMed ID: 30877234). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is predicted to alter canonical splice site by all splicing prediction programs (Alamut Visual Plus v1.6.1). RNA study suggests this variant results in abnormal splicing (Ben Aim et al. 2019. PubMed ID: 30877234). This variant is interpreted as pathogenic, likely pathogenic or a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/577461/). This variant is interpreted as likely pathogenic.