Submissions for variant NM_004168.4(SDHA):c.1741G>A (p.Gly581Arg)

gnomAD frequency: 0.00003  dbSNP: rs771111180

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693056	SCV000820910	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 581 of the SDHA protein (p.Gly581Arg). This variant is present in population databases (rs771111180, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma (PMID: 30877234; internal data). ClinVar contains an entry for this variant (Variation ID: 571817). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV001012918	SCV001173438	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The p.G581R variant (also known as c.1741G>A), located in coding exon 13 of the SDHA gene, results from a G to A substitution at nucleotide position 1741. The glycine at codon 581 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in one individual with head and neck paraganglioma; immunohistochemistry (IHC) of the tumor revealed absent SDHA and SDHB (Ben Aim L et al. J Med Genet, 2019 Aug;56:513-520), and multiple other probands with SDHA-related paraganglioma-pheochromocytoma syndrome (Ambry internal data). This variant was also detected with another SDHA pathogenic variant in gastrointestinal stromal tumor, which showed negative SDHB on IHC (Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799698	SCV002026137	likely pathogenic	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
Baylor Genetics	RCV004569314	SCV005055638	uncertain significance	Dilated cardiomyopathy 1GG	2024-01-04	criteria provided, single submitter	clinical testing
GeneDx	RCV004721557	SCV005328012	uncertain significance	not provided	2023-12-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35059314, 30877234)