Submissions for variant NM_004168.4(SDHA):c.1115C>G (p.Pro372Arg)

gnomAD frequency: 0.00004  dbSNP: rs141493530

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477582	SCV000553875	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 372 of the SDHA protein (p.Pro372Arg). This variant is present in population databases (rs141493530, gnomAD 0.009%). This missense change has been observed in individual(s) with paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 29177515). ClinVar contains an entry for this variant (Variation ID: 412361). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000575145	SCV000674917	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	The p.P372R variant (also known as c.1115C>G), located in coding exon 9 of the SDHA gene, results from a C to G substitution at nucleotide position 1115. The proline at codon 372 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in a patient with a unilateral pheochromocytoma diagnosed at age 24 and was classified as a variant of uncertain significance by the authors (Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001775824	SCV002009968	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001775824	SCV002013734	uncertain significance	not provided	2024-05-22	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; Observed in individuals with paraganglioma, neuroendocrine neoplasm, or ovarian cancer (PMID: 28384794, 29177515, 36947458, 38473309); This variant is associated with the following publications: (PMID: 29177515, 28384794, 36947458, 38473309)
Fulgent Genetics, Fulgent Genetics	RCV002481482	SCV002792593	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-09-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147470	SCV003836162	uncertain significance	Neurodegeneration with ataxia and late-onset optic atrophy	2022-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568119	SCV005055609	uncertain significance	Dilated cardiomyopathy 1GG	2024-02-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735547	SCV005354218	uncertain significance	SDHA-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The SDHA c.1115C>G variant is predicted to result in the amino acid substitution p.Pro372Arg. This variant has been reported as a variant of uncertain significance in an individual with head and neck paragangliomas (van der Tuin et al. 2018. PubMed ID: 29177515; Bausch et al. 2017. PubMed ID: 28384794) and in an individual with small bowel cancer (Riechelmann et al. 2023. PubMed ID: 36947458). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is interpreted as a variant of uncertain significance by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/412361/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.