Submissions for variant NM_004168.4(SDHA):c.1351C>T (p.Arg451Cys)

dbSNP: rs1553999752

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521022	SCV000617489	likely pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	Functional analysis found expression of variant is unable to rescue SDH and/or oxidative phosphorylation in SDH deficient E. coli and yeast cells (PMID: 10976639, 28724664); Heterozygous in affected individuals from two unrelated families presenting with ataxia, optic atrophy, and neurodegeneration with one family also with cardiomyopathy (PMID: 27683074, 10976639); A different missense change at this residue (R451H) has been reported in individuals with SDHA-related tumors (PMID: 26700204, 28724664, 29177515); 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: 28724664, 27683074, 10976639, 26700204, 29177515, 37215497)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063769	SCV001228630	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 451 of the SDHA protein (p.Arg451Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant complex II deficiency (PMID: 10976639, 27683074). It has also been observed to segregate with disease in related individuals. This variant is also known as C1375T (Arg408Cys). ClinVar contains an entry for this variant (Variation ID: 449389). 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. Experimental studies have shown that this missense change affects SDHA function (PMID: 10976639, 28724664). 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.
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799673	SCV002026132	uncertain significance	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
Ambry Genetics	RCV002384004	SCV002690194	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	The p.R451C variant (also known as c.1351C>T), located in coding exon 10 of the SDHA gene, results from a C to T substitution at nucleotide position 1351. The arginine at codon 451 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported (designated as 1375C>T, R408C) in two siblings with late-onset neurodegenerative disease, characterized by progressive optic atrophy, ataxia, and myopathy (Birch-Machin MA et al. Ann. Neurol., 2000 Sep;48:330-5). This alteration also segregated with disease in three individuals from a family with phenotype consistent with an autosomal dominant form of mitochondrial complex II deficiency (Courage C et al. Am. J. Med. Genet. A, 2017 Jan;173:225-230). Functional studies have demonstrated that p.R451C results in reduced protein activity (Birch-Machin MA et al. Ann. Neurol., 2000 Sep;48:330-5; Courage C et al. Am. J. Med. Genet. A, 2017 Jan;173:225-230; Bannon A et al. Clin. Cancer Res. 2017 Nov;23(21):6733-6743). Based on internal structural analysis, this variant likely disrupts the local structure of a ligand binding site in the SDHA protein (Sun F et al. Cell. 2005 Jul;121:1043-57; Iverson TM et al. J. Biol. Chem. 2012 Oct;287:35430-8; Inaoka DK et al. Int J Mol Sci. 2015 Jul;16:15287-308). Another alteration at this position, p.R451H (c.1352G>A), has been reported in individuals with SDHA-associated tumors (Toledo R et al. Clin. Cancer Res. 2016 05;22(9):2301-10; Bannon A et al. Clin. Cancer Res. 2017 Nov;23(21):6733-6743; van der Tuin K et al.J. Clin. Endocrinol. Metab. 2018 02;103(2):438-445). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
3billion	RCV003152716	SCV003842031	pathogenic	Mitochondrial complex II deficiency, nuclear type 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10976639). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.75). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000449389) and different missense changes at the same codon (p.Arg451His, p.Arg451Ser / ClinVar ID: VCV000581412, VCV000969346) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV001363197	SCV001559298	pathogenic	Neurodegeneration with ataxia and late-onset optic atrophy	2021-04-08	no assertion criteria provided	literature only