Submissions for variant NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)

gnomAD frequency: 0.00001  dbSNP: rs200397144

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163558	SCV000214116	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-25	criteria provided, single submitter	clinical testing	The p.R585W pathogenic mutation (also known as c.1753C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1753. The arginine at codon 585 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with paraganglioma, pheochromocytoma or gastrointestinal stromal tumor (Korpershoek E et al. J. Clin. Endocrinol. Metab. 2011 Sep;96:E1472-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Boikos SA et al. JAMA Oncol, 2016 Jul;2:922-8; Casey RT et al. Mol. Genet. Genomic Med. 2017 May;5:237-250; Tufton N et al. Endocr. Relat. Cancer 2017 Jul;24:L43-L49; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 Feb;103:438-445; Richter S et al. Genet Med, 2019 03;21:705-717). Another variant at the same codon, p.R585Q (c.1754G>A), has been detected in multiple individuals with paraganglioma or pheochromocytoma (Currás-Freixes M et al. J Med Genet, 2015 Oct;52:647-56; Ben Aim L et al. J Med Genet, 2019 08;56:513-520; Ambry internal data). Based on internal structural analysis, p.R585W is anticipated to result in a decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464783	SCV000553888	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 585 of the SDHA protein (p.Arg585Trp). This variant is present in population databases (rs200397144, gnomAD 0.005%). This missense change has been observed in individuals with paragangliomas and pheochromocytomas (PMID: 21752896, 23666964, 25720320, 28500238, 29177515, 30050099; internal data). ClinVar contains an entry for this variant (Variation ID: 160358). 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 expected to disrupt SDHA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg585 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 30877234), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000762143	SCV000892405	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
DASA	RCV001824123	SCV002073763	likely pathogenic	Neurodegeneration with ataxia and late-onset optic atrophy	2022-02-05	criteria provided, single submitter	clinical testing	The c.1753C>T;p.(Arg585Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 160358; PMID: 21752896; 23666964; 28500238; 25720320; 29177515; 30050099) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Succ_DH_flav_C) - PM1. The variant is present at low allele frequencies population databases (rs200397144 – gnomAD 0.00001314%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
GeneDx	RCV000762143	SCV002521995	likely pathogenic	not provided	2025-01-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22517557, 28196207, 22904323, 27011036, 29177515, 23666964, 28546994, 28500238, 25720320, 25394176, 32621582, 29978154, 30050099, 30877234, 20301715, 26198225, 36980917, 21752896, 35731023, 35171114, 35988656)
Myriad Genetics, Inc.	RCV000148027	SCV004045372	likely pathogenic	Paragangliomas 5	2023-04-24	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: 30050099, 28546994, 21752896, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003474794	SCV004200570	likely pathogenic	Dilated cardiomyopathy 1GG	2024-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824123	SCV005394833	pathogenic	Neurodegeneration with ataxia and late-onset optic atrophy	2024-09-23	criteria provided, single submitter	clinical testing	Variant summary: SDHA c.1753C>T (p.Arg585Trp) results in a non-conservative amino acid change located in the fumarate reductase/succinate dehydrogenase flavoprotein-like, C-terminal domain (IPR015939) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250906 control chromosomes. c.1753C>T has been reported in the literature in the heterozygous state in multiple individuals affected with pheochromocytoma, paraganglioma, and gastrointestinal stromal tumor (Richter_2022, Korpershoek_2011, Rattenberr_2013, Jahn_2022, Mandelker_2023, Casey_2017, Papathomas_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28546994, 35988656, 21752896, 36593350, 25720320, 23666964, 35171114). ClinVar contains an entry for this variant (Variation ID: 160358). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000148027	SCV000246127	pathogenic	Paragangliomas 5	2011-09-01	no assertion criteria provided	literature only
Counsyl	RCV000148027	SCV000785685	uncertain significance	Paragangliomas 5	2017-11-01	flagged submission	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765834	SCV000897229	uncertain significance	Leigh syndrome; Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5	2018-10-31	flagged submission	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000762143	SCV001807314	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000762143	SCV001956154	pathogenic	not provided		no assertion criteria provided	clinical testing