Submissions for variant NM_004168.4(SDHA):c.1787A>G (p.Asp596Gly)

gnomAD frequency: 0.00001  dbSNP: rs1126557

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000560589	SCV000651409	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 596 of the SDHA protein (p.Asp596Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 472358). 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.
Ambry Genetics	RCV000562151	SCV000674969	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The p.D596G variant (also known as c.1787A>G), located in coding exon 13 of the SDHA gene, results from an A to G substitution at nucleotide position 1787. The aspartic acid at codon 596 is replaced by glycine, an amino acid with similar properties. This alteration was identified via whole exome sequencing in conjunction with SDHA p.D135N in a three-year-old proband with combined complex II/III deficiency; however, the authors did not determine phase of the alterations, nor were any functional studies performed (Tan AP et al. Childs Nerv Syst 2018 Apr;34(4):601-603). 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.
GeneDx	RCV001755879	SCV002005707	uncertain significance	not provided	2023-10-30	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29488078)
Revvity Omics, Revvity	RCV001755879	SCV003819238	uncertain significance	not provided	2021-05-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409812	SCV004115354	uncertain significance	SDHA-related condition	2023-05-17	criteria provided, single submitter	clinical testing	The SDHA c.1787A>G variant is predicted to result in the amino acid substitution p.Asp596Gly. This variant has been reported along with a second in an individual with combined complex II/III deficiency (Tan et al. 2018. PubMed ID: 29488078). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-251576-A-G) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/472358/). 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	RCV001755879	SCV004220286	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00017 (6/35422 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with combined complex II/III deficiency (PMID: 29488078 (2018)). 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.