ClinVar Miner

Submissions for variant NM_017841.4(SDHAF2):c.232G>A (p.Gly78Arg)

dbSNP: rs113560320
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165971 SCV000216728 pathogenic Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing The p.G78R pathogenic mutation (also known as c.232G>A), located in coding exon 2 of the SDHAF2 gene, results from a G to A substitution at nucleotide position 232. The glycine at codon 78 is replaced by arginine, an amino acid with dissimilar properties. This mutation is considered a Dutch founder mutation and has been identified in multiple families with hereditary head and neck paragangliomas (HNPGL) (Hensen, EF et al. Clin Genet. 2012 Mar;81(3):284-8; Hao, HX et al. Science. 2009 Aug 28;325(5944):1139-42; Hoekstra AS et al. Oncotarget, 2017 Feb;8:14525-14536). In addition, this mutation co-segregated with disease in a Spanish family with HNPGL (Bayley, JP et al. Lancet Oncol. 2010 Apr;11(4):366-72) and was also observed in an apparently sporadic case of HNPGL in a patient with a right tympanic PGL (Piccini, V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55). Functional studies suggest that this mutation leads to a significant loss of flavination of SDHA, loss of activity of the succinate dehydrogenase complex, and reduced stability of SDHAF2 (Hao, HX et al. Science. 2009 Aug 28;325(5944):1139-42; Bezawork-Geleta A et al. FASEB J., 2014 Apr;28:1794-804). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000519058 SCV000617571 pathogenic not provided 2020-10-13 criteria provided, single submitter clinical testing Founder pathogenic variant in the Dutch population (Hensen 2012); Published functional studies demonstrate a damaging effect: variant results in a destabilized SDHAF2 protein and impairs SDHAF2-SDHA interaction (Hao 2009, Bezawork-Gelata 2014); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20972721, 19628817, 6286462, 28099933, 30050099, 24414418, 27587393, 22904323, 26627475, 23062074, 20071235, 21348866, 21224366, 25720320, 20938758, 23154507, 21082267, 21547462, 28384794, 20304625, 24739310, 31212687)
Labcorp Genetics (formerly Invitae), Labcorp RCV000639339 SCV000760911 pathogenic Hereditary pheochromocytoma-paraganglioma 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 78 of the SDHAF2 protein (p.Gly78Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with paraganglioma in multiple families, and is considered a founder mutation in the Dutch population (PMID: 19628817, 21224366, 6286462, 6264239, 21348866). This variant was also observed in an individual with paraganglioma (PMID: 22241717) and a Spanish family, segregating with paraganglioma (PMID: 20071235). The studies have shown a parent-of-origin inheritance pattern (paternal transmission) in these families (PMID: 19628817, 21224366, 20071235, 28099933), but the clinical significance of this is not established yet. ClinVar contains an entry for this variant (Variation ID: 401). Experimental studies have shown that this missense change impairs interaction with SDHA, reduces protein stability, and decreases SDHA flavination (PMID: 19628817, 24414418). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000000428 SCV004202956 pathogenic Paragangliomas 2 2023-01-04 criteria provided, single submitter clinical testing
OMIM RCV000000428 SCV000020576 pathogenic Paragangliomas 2 2012-03-01 no assertion criteria provided literature only
GeneReviews RCV000000428 SCV000054642 not provided Paragangliomas 2 no assertion provided literature only

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