Submissions for variant NM_004168.4(SDHA):c.287C>T (p.Thr96Ile)

gnomAD frequency: 0.00006  dbSNP: rs377620054

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231817	SCV000288134	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 96 of the SDHA protein (p.Thr96Ile). This variant is present in population databases (rs377620054, gnomAD 0.004%). 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: 239666). 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	RCV000569754	SCV000674939	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	The p.T96I variant (also known as c.287C>T), located in coding exon 3 of the SDHA gene, results from a C to T substitution at nucleotide position 287. The threonine at codon 96 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000663057	SCV000786109	uncertain significance	Paragangliomas 5	2018-02-26	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761150	SCV000891066	uncertain significance	B-lymphoblastic leukemia/lymphoma with hypodiploidy	2017-07-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663057	SCV004018622	uncertain significance	Paragangliomas 5	2023-04-21	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.
Baylor Genetics	RCV004567733	SCV005055595	uncertain significance	Dilated cardiomyopathy 1GG	2024-03-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000786220	SCV005396415	uncertain significance	not provided	2024-05-07	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; Has not been previously published as pathogenic or benign to our knowledge
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786220	SCV000924958	uncertain significance	not provided	2016-05-27	no assertion criteria provided	provider interpretation	p.Thr96Ile (c.287C>T) in exon 3 of the SDHA gene (NM_004168.2) Seen in a patient with multiple unexplained VF arrests. Given the lack of case data and the poor fit for the phenotype, we consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing").