Submissions for variant NM_000551.4(VHL):c.224TCT[1] (p.Phe76del)

dbSNP: rs5030648

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469401	SCV000553395	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the VHL protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hippel-Lindau syndrome (PMID: 12114495, 17661816, 18446368, 20064270, 20151405, 20567917, 22357542, 23632291, 27439424, 27527340). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 223166). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003389711	SCV000805328	pathogenic	VHL-related disorder	2022-09-11	criteria provided, single submitter	clinical testing	The VHL c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant has been previously reported in the heterozygous state in individuals or affected family members with Von Hippel-Lindau syndrome (see for example Hes et al. 2007. PubMed ID: 17661816; Ong et al. 2007. PubMed ID: 17024664, Supplementary Table S1; Nordstrom-O'Brien et al. 2010. PubMed ID: 20151405, Supplementary Table S1; Leonardi et al. 2011. PubMed ID: 21463266, Supplementary material; Wu et al. 2012. PubMed ID: 22357542; also reported with differences in the cDNA nomenclature in Wong et al. 2016. PubMed ID: 27527340; Pandit et al. 2016. PubMed ID: 27539324; Lomte et al. 2018. PubMed ID: 29124493). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
CIViC knowledgebase, Washington University School of Medicine	RCV000208790	SCV001192830	pathogenic	Von Hippel-Lindau syndrome		criteria provided, single submitter	curation	The inframe variant, F76del, is pathogenic for Von Hippel-Lindau Disease. EID5682 shows a large family with the variant cosegregating with affected individuals (PP1). However, confirmed de novo mutations are also described EID5340 (PS2). Both are supported by several other reports with familial and sporadic VHL and this variant. This inframe deletion is not in a repetitive region (PM4) and absent from gnomAD v2.1 (PM2).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208790	SCV001365606	pathogenic	Von Hippel-Lindau syndrome	2019-12-03	criteria provided, single submitter	clinical testing	The p.Phe76del variant in VHL has been reported in >15 individuals with clinical features of Von Hippel-Lindau syndrome and segregated with disease in >5 affected individuals from several families (Crossey 1994, Cybulski 2002, Gomy 2010, Hes 2007, Jia 2013, Lee 2016, Nordstrom-Obrien 2010, Pandit 2016, Rasmussen 2010, Wang 2018, Wong 2016, Wu 2012, Zhang 2008). It was also identified as a de novo occurrence in 1 individual, though maternity and paternity were not confirmed (Jia 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 223166) and was absent from large population studies. This variant is a deletion of 1 amino acid at position 76 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Von Hippel- Lindau syndrome. ACMG/AMP criteria applied: PS4, PM2, PM6, PP1_Moderate, PM4_Supporting.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000208790	SCV001499822	pathogenic	Von Hippel-Lindau syndrome	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000679023	SCV001774350	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region in the critical beta sandwich region of the beta domain (Yuen 2009); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on protein structure/function; Also known as c.440_442del, p.(F147del); p.(F117del); This variant is associated with the following publications: (PMID: 7987306, 20064270, 20567917, 12624160, 8730290, 8634692, 9829911, 29961792, 30072823, 31528828, 27682873, 28036268, 27539324, 27527340, 27439424, 12114495, 17661816, 18446368, 20151405, 22357542, 7728151, 7553625, 8956040, 9829912, 10631138, 8641976, 7977367, 23632291, 25867206, 23011899, 11331613, 29124493, 29616089, 29748190, 32179488, 33720516, 33107222, 32003155)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000208790	SCV002512257	pathogenic	Von Hippel-Lindau syndrome	2021-07-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate, PP1 very strong
Ambry Genetics	RCV002444839	SCV002734017	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-28	criteria provided, single submitter	clinical testing	The c.227_229delTCT pathogenic mutation (also known as c.226_228del TTC or p.F76del) is located in coding exon 1 of the VHL gene. This pathogenic mutation results from an in-frame TCT deletion at nucleotide positions 227 to 229. This results in the in-frame deletion of a phenylalanine at codon 76. This pathogenic variant has been identified in numerous individuals and families diagnosed with VHL (Rocha J et al. J. Med. Genet. 2003 Mar; 40(3):e31; Sgambati M et al. Am. J. Hum. Genet. 2000 Jan; 66(1):84-91; Gomy I et al. Fam. Cancer. 2010 Dec; 9(4):635-42; Hes F et al. Clin. Genet. 2007 Aug; 72(2):122-9; Rasmussen A et al. BMC Med. Genet. 2010 Jan 12;11:4; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Wang Y et al. Oncol Lett. 2018 Apr;15:4882-4890). Molecular dynamics studies indicate that the phenyalanine at amino acid position 76, which is deleted by this alteration, plays a key role in the structural integrity of the beta-domain of the VHL protein (Limaverde-Sousa G et al. Proteins. 2013 Feb; 81(2):349-63). Of note, this pathogenic variant may be referred to as c.224_226delTCT in some literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV000208790	SCV004175276	likely pathogenic	Von Hippel-Lindau syndrome	2022-11-09	criteria provided, single submitter	clinical testing	The VHL c.227_229del variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM4, PM6, PP1, PP4) The VHL c.227_229del variant results in an inframe deletion in exon 1/3. This variant has been reported in 9 unrelated individuals with a clinical presentation of von Hippel-Lindau syndrome (PMID: 7987306, 27527340, 29616089, 32179488, 33720516) (PS4_Moderate). This variant is absent from population databases (PM2). This variant is predicted to alter the length of the protein produced by this gene due to an inframe deletion variant in a nonrepeat region (PM4). This variant has been identified as a de novo variant in at least one affected patient with no family history of this condition (PMID: 8641976, 23632291) (PM6). This variant is reported to co-segregate with disease in one family (PMID: 23143947) (PP1). The clinical features of this case are highly specific for the VHL gene (PP4). This variant is in dbSNP (rs5030648), has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID:223166) and has been reported as disease-causing in HGMD (CD941805).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208790	SCV000264675	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing