Submissions for variant NM_004168.4(SDHA):c.1724C>T (p.Ala575Val)

gnomAD frequency: 0.00004  dbSNP: rs750327309

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467983	SCV000553894	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 575 of the SDHA protein (p.Ala575Val). This variant is present in population databases (rs750327309, 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: 412376). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. 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.
GeneDx	RCV000487393	SCV000570527	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Observed in a patient with multiple primary tumors who also harbored pathogenic variants in CHEK2 and HOXB13 (PMID: 34711244); 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 reported as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 34711244)
Ambry Genetics	RCV000572994	SCV000674974	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-18	criteria provided, single submitter	clinical testing	The p.A575V variant (also known as c.1724C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1724. The alanine at codon 575 is replaced by valine, 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.
Counsyl	RCV000663257	SCV000786484	uncertain significance	Paragangliomas 5	2018-05-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572994	SCV002527728	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268094	SCV002550449	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663257	SCV004018574	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	RCV003476132	SCV004202386	uncertain significance	Dilated cardiomyopathy 1GG	2024-03-27	criteria provided, single submitter	clinical testing