Submissions for variant NM_004168.4(SDHA):c.563G>A (p.Arg188Gln)

gnomAD frequency: 0.00004  dbSNP: rs139881415

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000518854	SCV000619459	uncertain significance	not provided	2021-03-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15989954, 28724664, 23282968, 32741965)
Invitae	RCV000531381	SCV000651447	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 188 of the SDHA protein (p.Arg188Gln). This variant is present in population databases (rs139881415, gnomAD 0.01%). This missense change has been observed in individuals with gastrointestinal stromal tumor syndrome and/or paragangliomas (PMID: 32741965; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 450839). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. This variant disrupts the p.Arg188 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 23282968; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001024356	SCV001186356	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-15	criteria provided, single submitter	clinical testing	The p.R188Q variant (also known as c.563G>A), located in coding exon 5 of the SDHA gene, results from a G to A substitution at nucleotide position 563. The arginine at codon 188 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a paraganglioma or gastrointestinal stromal tumor (Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Rana HQ et al. Cancers (Basel), 2024 Feb;16:; Ambry internal data). This amino acid position is highly 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000518854	SCV002774736	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330742	SCV004039337	uncertain significance	not specified	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: SDHA c.563G>A (p.Arg188Gln) results in a conservative amino acid change located in the FAD-dependent oxidoreductase 2, FAD binding domain (IPR003953) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.563G>A has been reported in the literature in an individual affected with Paraganglioma (Greenberg_2020). This report does not provide unequivocal conclusions about association of the variant with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32741965). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003335449	SCV004043212	likely pathogenic	Paragangliomas 5	2023-09-28	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: 32741965, Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data].