ClinGen - only curated for other conditions, AD hereditary pheochromocytoma-paraganglioma (definitive), AR Leigh syndrome (Moderate). GenCC - Strong (Invitae). Babyseq, none. HGMD curations below
Birch-Machin 2000, 10976639: descr. as C1375T Arg408Cys, seq. in Fig. 1. Variant found in two affected siblings (II-4 and II-5) with progressive neurodegenerative disease with bilateral optic atrophy with cupped optic disks (but no retinopathy), myopathy, and ataxia. No evidence of cardiac involvement. These individuals had a 50% decrease in complex II and SDH activities in skeletal muscle. Patient II-3 is clinically unaffected and has normal complex II activities, and the variant was absent in this individual. (1 AFFECTED, 1 UNAFFECTED SEG). Mutation construct in e coli, no membrane-associated succinate-quinone (complex II) or succinate-dye (SDH) reductase activities and no histidyl-FAD was detected in cellstransformed with the mutant plasmid (pRC4) (Fig 2a). AD CASE, 1 AFFECTED, 1 UNAFFECTED SEG. 0.5 POINT NON-PATIENT CELLS FUNCTIONAL + 0.5 VARIANT POINTS
Courage 2017 PMID: 27683074 - The proband II.5 presented early in childhood with clumsiness, nystagmus in one eye, cramps in foot and speech impediment. AT 15 years he had worsening ocular paresis, nystagmus, pyrmidal signs and ataxia, cardiomyopathy w/ cardiomegaly. Optic atrophy dx at 47y. Cardiomyopathy progresse to DCM w/ EJ 48% at 54y. Son III:2 with generalized fatigue at 8mos, dilative cardiomyopathy, at 2.5 hospitalized due to recurrent vomiting and had slight blood lactate elevation, at 30y cardiomyopathy and bilateral optic atrophy. Daughter III:3 stillborn. III:4 deceased at 7mos due to cardiac insufficiency, with marginally elevated lactate in blood and urinary 3-methylglutaconic and 3OH-methylglutaconic. Autopsy showed severe dilation of cardiomoypathy with abnoral increase of mitochondria. Fibroblast cultures of proband showed isolated complex II deficiency. Western blot showed the protein was at normal levels indicating it is stable. COUNTING 1 AD PROBAND AND 2 AFFECTED SEGREGATIONS (III:3 AND III:4). 0.5 VARIANT POINT + 1 POINT PATIENT CELL FUNCTIONAL ALTERNATION
PMID: 27847310 The hypothesis was that deficiency in SDH activity associated w/ neurodegenerative diseases result in sustained cellular respiration. Found that inhibitiion by 3-NPA in differentited LUHMES cells and overexpression in HAP1 cells induced succinate accumiulation (Fig 5a and b) and resulted in sustained cellular respiration (Fig 5c and d). 1 POINT BIOCHEMICAL FUNCTION
PMID: 28724664 - notes from Fabric team: p.Arg451His affects the SDHA protein functions. Added by Megha - yeast complementation assay. R444C in yeast. R444C described as a LOF variant - unable to grow on glycerol, showed decreased oxygen consumption and sdh2 protein and disrupted flavin binding. PS3 applies. 1 POINT NON-HUMAN MODEL ORGANISM
Arg662Cys 1 allele gnomAD REVEL: 0.916
PMID: 33471299 Adolescent girl of Arab ancestry with golbal DD, ID, childhood onset progressive bilateral optic atrophy. Normal cardiac exam at 12y. Variant is de novo. Biochem analysis of fibroblasts showed decreased complex II activity. Variant found via trio WES. Table 2 shows a nice summary of this variant. AD DE NOVO CASE W/ MAT/PAT, BIOCHEM (PP4). 0.5 VARIANT POINT + 0.5 DE NOVO + 1 POINT PATIENT CELLS
PMID: 36305856
p.[Tyr55His];[Arg662Cys] in supplement, in patient 86, the Tyr55His variant is a 2 star B/LB variant. Phenotype is mitochondrial related disorder. Per mmc4 supp, onset <1y, seizures, DD, progressive symptoms, cerebellar hypoplasia and atrophy. AD CASE 0.5 POINTS
INFANTILE ONSET
Alston CL, et al., 2012, PMID: 22972948 - The encoded protein interacts with one gene product (SDHB) whose dysfunction is known to cause Leigh syndrome. (FROM CLINGEN LEIGH SYNDROME CURATION) 1 POINT PROTEIN INTERACTION.
Clinical ValidityPoints Total
SUMMARY 7.5 POINTS:
Variant evidence 2.5 points. Segregation evidence was insufficient to score (3 affected, 1 unaffected seg)
Experimental evidence 5 points: 2 point functional (1 biochem + 1 protein interaction), 2 point functional alteration, 1 point non-human model organism)
PMID: 33162331 has a great summary of the experimental evidence from the papers in the clinical validity scoring section
Western blot demonstrated no reductin in steady state levels of SDHA protein (no effect on protein stability implying a qualitative defect
Crystal strucure indicates that Arg451 residue is critical within the succinate binding pocket
E. coli study - the Arg451Cys variant prevents FAD cofactor forming a covalent bond within the critical histidine residue of SDHA, thus rendering the enzyme inactive.
Second hypothesis is that the variant Arg451Cys that succinate is still able to bind to the remining residues but a greater concentration of substrate is required due to decreased affinity. Ubiquinone remains able to bind to complex II in spite of the variant but cannot be reduced, this would consistent w/ a dominant pathomechanism
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Variable. Some individuals present in early childhood, potentially prenatally and others present in adulthood. Progressive .
Severity
Moderate to severe
Clinical Features
Variable
optic atrophy, ocular paresis, nystagmus
Ataxia
myopathy
Cardiomyopathy (can be variable onset, with severe cardiomyopathy at 7mos in one individual)
The SDHA gene is associated with several diseases. Autosomal dominant hereditary pheochromocytoma-paraganglioma syndrome is characterized by an increased risk of multiple paragangliomas and pheochromocytoma tumors that may be multifocal, recurrent, early onset, extra-adrenal, and/or metastatic (PMID: 20301715). Autosomal recessive complex II deficiency is characterized by infant or early childhood onset of developmental delay, developmental regression, cardiomyopathy, abnormal brain MRI, hypotonia, ataxia, and respiratory distress. Autosomal dominant complex II deficiency is characterized by variable onset of optic atrophy, developmental delays, ocular paresis, ataxia, myopathy, and cardiomyopathy, and other features, with only two autosomal dominant variants, p.Arg451Cys and p.Arg662Cys, reported to date (PMID: 33162331, 33471299, 36305856).