Submissions for variant NM_017841.4(SDHAF2):c.52A>G (p.Arg18Gly)

gnomAD frequency: 0.00004  dbSNP: rs200911550

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568645	SCV000675039	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-20	criteria provided, single submitter	clinical testing	The p.R18G variant (also known as c.52A>G), located in coding exon 2 of the SDHAF2 gene, results from an A to G substitution at nucleotide position 52. The arginine at codon 18 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687293	SCV000814852	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 18 of the SDHAF2 protein (p.Arg18Gly). This variant is present in population databases (rs200911550, gnomAD 0.006%). This missense change has been observed in individual(s) with SDHAF2-related conditions (PMID: 32830346). ClinVar contains an entry for this variant (Variation ID: 41836). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV000034763	SCV001992704	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with atherosclerosis (PMID: 22703879); This variant is associated with the following publications: (PMID: 22703879)
Baylor Genetics	RCV003473261	SCV004202945	uncertain significance	Paragangliomas 2	2024-02-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034763	SCV004220257	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an unaffected individual (PMID: 22703879 (2012)). The frequency of this variant in the general population, 0.000091 (3/33120 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 benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on SDHAF2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034763	SCV000043482	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.