3-10142080-A-G
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM6PM1PS3_SupportingPP3PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser) is a missense variant predicted to cause substitution of Asparagine by Serine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 16 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 15.25, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:728151; 23842656; 25952756; 21463266; 25078357; 8634692; 23407287; 8707293; 8730290; 18067796; 12114495; 12202531; 17024664; 28388566; 18446368; 10567493; 29294023; 11850829) This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VHL (PMID:12114495) (PM6). This variant is also seen 4 times in cancerhotspots.org, which meets the criteria of PM1_Supporting, when using somatic data to inform a germline variant curation. However, as the variant resides in the first Beta domain of VHL, a critical functional domain, it meets the full moderate criteria of (PM1). Functional data shows this variant did not alter expression of HIF1a (102% for HIF1α , similar to the truncating control used) and 86% expression for HIF2α (PS3_Supporting; PMID:21715564). The computational predictor REVEL gives a score of 0.767, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020131/MONDO:0008667/078
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
Publications
- pheochromocytomaInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- von Hippel-Lindau diseaseInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
- renal cell carcinomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- autosomal recessive secondary polycythemia not associated with VHL geneInheritance: AR Classification: STRONG Submitted by: Ambry Genetics
- Chuvash polycythemiaInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | c.233A>G | p.Asn78Ser | missense_variant | Exon 1 of 3 | ENST00000256474.3 | NP_000542.1 | |
| VHL | NM_001354723.2 | c.233A>G | p.Asn78Ser | missense_variant | Exon 1 of 3 | NP_001341652.1 | ||
| VHL | NM_198156.3 | c.233A>G | p.Asn78Ser | missense_variant | Exon 1 of 2 | NP_937799.1 | ||
| VHL | NR_176335.1 | n.303A>G | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VHL | ENST00000256474.3 | c.233A>G | p.Asn78Ser | missense_variant | Exon 1 of 3 | 1 | NM_000551.4 | ENSP00000256474.3 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:5
The variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser) is a missense variant predicted to cause substitution of Asparagine by Serine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 16 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 15.25, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:728151; 23842656; 25952756; 21463266; 25078357; 8634692; 23407287; 8707293; 8730290; 18067796; 12114495; 12202531; 17024664; 28388566; 18446368; 10567493; 29294023; 11850829) This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VHL (PMID:12114495) (PM6). This variant is also seen 4 times in cancerhotspots.org, which meets the criteria of PM1_Supporting, when using somatic data to inform a germline variant curation. However, as the variant resides in the first Beta domain of VHL, a critical functional domain, it meets the full moderate criteria of (PM1). Functional data shows this variant did not alter expression of HIF1a (102% for HIF1α , similar to the truncating control used) and 86% expression for HIF2α (PS3_Supporting; PMID:21715564). The computational predictor REVEL gives a score of 0.767, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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.
not provided Pathogenic:5
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)
The VHL c.233A>G (p.Asn78Ser) variant has been reported in the published literature in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 15300849 (2004), 19464396 (2009), 23842656 (2013), 27439424 (2016), 28388566 (2017), 32742360 (2020), 33720516 (2021)). This variant has also been identified in individuals with renal cell carcinoma (PMID: 35441217 (2002), 37405915 (2023)) and pheochromocytoma and paraganglioma (PPGL) (PMID: 37529773 (2023)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 11739384 (2022), 19602254 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as pathogenic.
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
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). This variant is not present in population databases (gnomAD no frequency). 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 also known as N149S. ClinVar contains an entry for this variant (Variation ID: 93326). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 19602254, 21454469). For these reasons, this variant has been classified as Pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:1
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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at