Submissions for variant NM_017841.4(SDHAF2):c.205C>T (p.Arg69Cys)

gnomAD frequency: 0.00004  dbSNP: rs532255760

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219985	SCV000273640	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The p.R69C variant (also known as c.205C>T), located in coding exon 2 of the SDHAF2 gene, results from a C to T substitution at nucleotide position 205. The arginine at codon 69 is replaced by cysteine, an amino acid with highly dissimilar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468611	SCV000552837	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 69 of the SDHAF2 protein (p.Arg69Cys). This variant is present in population databases (rs532255760, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 230189). 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 disruptive. 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	RCV002298531	SCV002588338	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	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 published as pathogenic or benign to our knowledge
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444221	SCV004171523	uncertain significance	Paragangliomas 2	2023-10-26	criteria provided, single submitter	clinical testing	The SDHAF2 c.205C>T (p.Arg69Cys) missense change has a maximum subpopulation frequency of 0.0081% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in individuals with SDHAF2-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000468611	SCV004837007	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 69 of the SDHAF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has been identified in 7/281894 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.