Submissions for variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser)

dbSNP: rs5030804

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000254892	SCV000111077	pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000254892	SCV000322000	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: an unstable protein resulting in up-regulation of HIF-2a and Glut-1, down-regulation of P27, and the disruption of pVHL and hVDU1 interactions in vitro (Li et al., 2002; Bangiyeva et al., 2009; Rechsteiner et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 446A>G; This variant is associated with the following publications: (PMID: 8730290, 16775032, 8707293, 19602254, 18836774, 23757202, 8634692, 7553625, 15300849, 17661816, 11409863, 12202531, 7591282, 10567493, 17024664, 14767899, 21362373, 9452106, 21454469, 11739384, 21715564, 10408776, 7728151, 25563310, 23842656, 27530247, 27439424, 26984080, 27527340, 12114495, 15109448, 30338240, 30787465, 8956040, 33720516, 18446368, 20233476, 28559085, 32742360)
Ambry Genetics	RCV000492165	SCV000580971	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	clinical testing	The p.N78S pathogenic mutation (also known as c.233A>G) is located in coding exon 1 of the VHL gene and results from an A to G substitution at nucleotide position 233. The asparagine at codon 78 is replaced by serine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals and families with VHL and has been shown to co-segregate with disease (Chen et al. Hum Mut. 1995; 5(1): 66-75; Zbar et al. Hum Mut. 1996 8:348-357; Cybulski et al. J Med Genet. 2002 Jul;39(7):E38; Zhang et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8; Siu et al. Chin Med J (Engl). 2011 Jan;124(2):237-41; Lee JS et al. BMC Med. Genet. 2016 07;17(1):48; Cingoz S et al. Fam Cancer 2013 Mar;12(1):111-7; Lin G et al. Exp Ther Med 2020 Aug;20(2):1237-1244; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805). In one study, the p.N78S mutation, a type1 VHL protein mutant, was expressed in VHL-negative renal cell carcinoma cell lines. The authors concluded that VHL has both HIF-á dependent and HIF-á independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease (Bangiyeva et al. BMC Cancer 2009. Jul 14;9:229). Of note, this alteration is also referred to as 446A>G (Asn149Ser) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001034687	SCV000626871	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This variant is also known as N149S. This missense change has been observed in individual(s) with von Hippel–Lindau disease (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 78 of the VHL protein (p.Asn78Ser). ClinVar contains an entry for this variant (Variation ID: 93326). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 19602254, 21454469). 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) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function.
Counsyl	RCV000079207	SCV000785647	pathogenic	Von Hippel-Lindau syndrome	2017-10-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000254892	SCV000805330	pathogenic	not provided	2016-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079207	SCV001442590	pathogenic	Von Hippel-Lindau syndrome	2020-10-28	criteria provided, single submitter	clinical testing	Variant summary: VHL c.233A>G (p.Asn78Ser) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta domain (IPR024053) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230680 control chromosomes (gnomAD). c.233A>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome and has been shown to co-segregate with disease in different families (e.g. Zbar_1996, Cybulski_2002, Dollfus_2002, Huang_2004). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant impairs protein function and stability and results in compromised tight junction formation, disorganized cell morphology and increased HIF (hypoxia-inducible factor) activation (e.g. Bangiyeva_2009, Bond_2011). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000079207	SCV000264678	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV000079207	SCV001950147	pathogenic	Von Hippel-Lindau syndrome	2019-07-10	no assertion criteria provided	clinical testing