Submissions for variant NM_004168.4(SDHA):c.1177G>A (p.Val393Met)

dbSNP: rs372989971

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001010145	SCV001170299	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-29	criteria provided, single submitter	clinical testing	The p.V393M variant (also known as c.1177G>A), located in coding exon 9 of the SDHA gene, results from a G to A substitution at nucleotide position 1177. The valine at codon 393 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in an individual diagnosed with a carotid paraganglioma at age 63 who had no family history of paraganglioma or pheochromocytoma (Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212). 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.
Illumina Laboratory Services, Illumina	RCV001156140	SCV001317626	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001156141	SCV001317627	likely benign	Hereditary pheochromocytoma-paraganglioma	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001156142	SCV001317628	uncertain significance	Leigh syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001238661	SCV001411486	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 393 of the SDHA protein (p.Val393Met). This variant is present in population databases (rs372989971, gnomAD 0.006%). This missense change has been observed in individual(s) with paraganglioma (PMID: 28384794). ClinVar contains an entry for this variant (Variation ID: 818500). 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.
PreventionGenetics, part of Exact Sciences	RCV003432990	SCV004117911	uncertain significance	SDHA-related condition	2023-01-19	criteria provided, single submitter	clinical testing	The SDHA c.1177G>A variant is predicted to result in the amino acid substitution p.Val393Met. This variant was reported in an individual with a carotid paraganglioma (eTable 1 in Bausch et al. 2017. PubMed ID: 28384794). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-235371-G-A) and has been interpreted as likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/818500/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478607	SCV004220260	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with personal history of a carotid paraganglioma (PMID: 28384794 (2017)). The frequency of this variant in the general population, 0.000012 (3/251388 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.