ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) (rs104893829)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656990 SCV000149653 likely benign not provided 2020-11-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25115387, 18209888, 23327821, 10408776, 18434768, 22067401, 8956040, 29871882, 29415044, 15932632, 20454689, 9681856, 23477374, 25883647, 27530247, 15177666, 23990664, 11409863, 23142018, 15383938, 24969085, 18836774, 15607616, 10340905, 12056827, 17661816, 20447124, 18475055, 15324605, 20151405, 10761708, 8634692, 10567493, 12414898, 19228690, 24132471, 25157968, 23639312, 17454194, 24986515, 25424545, 24142049, 27051783, 23990666, 22234250, 11739384, 27146957, 27527340, 28503092, 25637381, 9829911, 11106358, 8707293, 19906784, 29790589, 31087189, 17997830, 19408298, 7553625, 17264095, 30877234)
CSER _CC_NCGL, University of Washington RCV000002321 SCV000190677 likely benign Von Hippel-Lindau syndrome 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics RCV000115744 SCV000212872 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-29 criteria provided, single submitter clinical testing The p.P81S variant (also known as c.241C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 241. The proline at codon 81 is replaced by serine, an amino acid with similar properties. This alteration has been described as both a low-penetrance mutation in VHL type 1 families (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Hes FJ et al. J. Med. Genet. 2000 Dec;37:939-43; Kondo K et al. Hum. Mol. Genet. 1995 Dec;4:2233-7; Yoshida M et al. Jpn J Cancer Res. 2000 Feb;90:204-212; Zbar B et al. Hum. Mutat. 1996;8:348-57; Alosi D et al. Curr. Genomics. 2017 Feb;18:93-103) and as a nonpathogenic alteration (Erlic Z et al. J Clin Endocrinol Metab. 2010 Jan;95:308-13). The p.P81S alteration was found to co-segregate with another missense alteration in a large VHL type 2C family with highly penetrant disease and may represent a disease modifier (Weirich G et al. J. Clin. Endocrinol. Metal. 2002 Nov;87:5241-6). Functional studies indicate this variant does not significantly affect HIF1 interaction (Knauth K et al. J. Biol. Chem. 2009 Apr;284:10514-22), but has deleterious effects on other aspects of VHL function such as reduced DNA damage response, resistance to ionizing radiation-induced apoptosis and impaired ubiquitination of the downstream target VDU1 (DeSimone MC et al. J. Natl. Cancer Inst. 2013 Sep;105:1355-64; Li Z et al. J. Biol. Chem. 2002 Feb;277:4656-62). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001080004 SCV000254650 benign Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-12-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000213077 SCV000540657 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several reports describe as LB/non-pathogenic; ExAC: 0.04% (19/53684) European chromosomes
PreventionGenetics,PreventionGenetics RCV000656990 SCV000805331 likely benign not provided 2017-10-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000002321 SCV000890934 uncertain significance Von Hippel-Lindau syndrome 2021-02-11 criteria provided, single submitter clinical testing The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/3-10183772-C-T?dataset=gnomad_r2_1). The variant is located in a mutational hotspot (PM1; COSMIC database). In silico tools are not in agreement about the effect of this variant on protein function, and functional studies also show mixed effects. Some functional studies have concluded that the variant behaves similar to the wild-type (Knauth 2009), whereas others suggest this variant may lead to reduced DNA damage response and resistance to ionizing radiation induced apoptosis (Li 2002, Desimone 2013). The Pro81Ser change has been reported in several individuals and families with Von Hippel Lindau-related cancers (PS4; Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). In one family, this variant was found to co-occur with a large deletion of the entire VHL gene in trans in affected individuals (BS4, BP2; Erlic 2009). In another family with several affected individuals, the variant was found to co-segregate in cis with another missense change in VHL (BP2; Weirich 2002). Since supporting evidence is conflicting, the clinical significance of this alteration remains unclear. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS4, PM1, BS4, BP2.
Gharavi Laboratory,Columbia University RCV000656990 SCV000920742 likely benign not provided 2018-09-16 criteria provided, single submitter research
Mendelics RCV000002321 SCV001136311 uncertain significance Von Hippel-Lindau syndrome 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656990 SCV001153778 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002321 SCV001311112 uncertain significance Von Hippel-Lindau syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
University Health Network Clinical Genomics Labs,University Health Network RCV000002321 SCV001950150 uncertain significance Von Hippel-Lindau syndrome 2020-09-08 criteria provided, single submitter clinical testing
OMIM RCV000002321 SCV000022479 pathogenic Von Hippel-Lindau syndrome 2002-11-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002321 SCV000053257 likely benign Von Hippel-Lindau syndrome 2015-10-02 no assertion criteria provided clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000002321 SCV000264680 uncertain significance Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000418681 SCV000505320 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only

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