Submissions for variant NM_004168.4(SDHA):c.424A>G (p.Met142Val)

gnomAD frequency: 0.00003  dbSNP: rs776848209

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457452	SCV000553864	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 142 of the SDHA protein (p.Met142Val). This variant is present in population databases (rs776848209, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SDHA-related conditions (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 412352). 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.
GeneDx	RCV001755708	SCV002006217	uncertain significance	not provided	2021-03-22	criteria provided, single submitter	clinical testing	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
Ambry Genetics	RCV002329086	SCV002626964	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-16	criteria provided, single submitter	clinical testing	The p.M142V variant (also known as c.424A>G), located in coding exon 4 of the SDHA gene, results from an A to G substitution at nucleotide position 424. The methionine at codon 142 is replaced by valine, an amino acid with highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002481481	SCV002793232	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy	2021-11-11	criteria provided, single submitter	clinical testing
Clinical Genomics Program, Stanford Medicine	RCV003987544	SCV004804532	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2021-06-03	criteria provided, single submitter	clinical testing	The p.Met142Val variant in the SDHAgene has not been previously reported in association with disease.•This variant has been identified in 4/24,758 African/African-American chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency.•Computational tools predict that this variant is deleterious; however, the accuracy of in silicoalgorithms is limited.•These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Met142Val variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP3]