Submissions for variant NM_004168.4(SDHA):c.704T>C (p.Ile235Thr)

gnomAD frequency: 0.00015  dbSNP: rs144513891

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203953	SCV000262238	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 235 of the SDHA protein (p.Ile235Thr). This variant is present in population databases (rs144513891, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 221076). 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.
Counsyl	RCV000410184	SCV000489501	uncertain significance	Paragangliomas 5	2016-10-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562815	SCV000674949	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The p.I235T variant (also known as c.704T>C), located in coding exon 6 of the SDHA gene, results from a T to C substitution at nucleotide position 704. The isoleucine at codon 235 is replaced by threonine, an amino acid with similar properties. 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.
Fulgent Genetics, Fulgent Genetics	RCV002478742	SCV000897220	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-09-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197548	SCV001368327	uncertain significance	Leigh syndrome	2019-06-12	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
GeneDx	RCV001582713	SCV001818611	uncertain significance	not provided	2023-10-08	criteria provided, single submitter	clinical testing	Identified in an individual with advanced cancer; additional clinical and family history not provided (PMID: 28873162); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 28873162)
Sema4, Sema4	RCV000562815	SCV002527764	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410184	SCV004045353	uncertain significance	Paragangliomas 5	2023-04-24	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001582713	SCV004220316	uncertain significance	not provided	2023-02-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00024 (12/50616 chromosomes in North-Western European subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with an unspecified phenotype (PMID: 24448499 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV004567488	SCV005055581	uncertain significance	Dilated cardiomyopathy 1GG	2024-03-21	criteria provided, single submitter	clinical testing