Submissions for variant NM_004168.4(SDHA):c.1652C>T (p.Thr551Met)

gnomAD frequency: 0.00002  dbSNP: rs181238392

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458208	SCV000553921	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 551 of the SDHA protein (p.Thr551Met). This variant is present in population databases (rs181238392, gnomAD 0.01%). 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: 412397). 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	RCV000569746	SCV000674999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The p.T551M variant (also known as c.1652C>T), located in coding exon 12 of the SDHA gene, results from a C to T substitution at nucleotide position 1652. The threonine at codon 551 is replaced by methionine, 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	RCV000662939	SCV000785896	uncertain significance	Paragangliomas 5	2018-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002475896	SCV002777502	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-08-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662939	SCV004018575	uncertain significance	Paragangliomas 5	2023-04-20	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	RCV004568123	SCV005056597	uncertain significance	Dilated cardiomyopathy 1GG	2023-11-14	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000662939	SCV004228538	not provided	Paragangliomas 5		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-11-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.