Submissions for variant NM_000551.4(VHL):c.574C>T (p.Pro192Ser)

dbSNP: rs28940300

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236065	SCV000293497	uncertain significance	not provided	2021-09-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed on the opposite allele (in trans) with a pathogenic variant in an individual with polycythemia (Pastore 2003); Also known as c.787C>T p.(P263S) and p.(P233S); This variant is associated with the following publications: (PMID: 18836774, 24115288, 24166983, 11536052, 26957611, 12844285, 29607586)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704063	SCV000832996	likely pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 192 of the VHL protein (p.Pro192Ser). This variant is present in population databases (rs28940300, gnomAD 0.002%). This missense change has been observed in individual(s) with familial erythrocytosis type 2 (Chuvash polycythemia) (PMID: 12844285). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2234). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001024480	SCV001186503	uncertain significance	Hereditary cancer-predisposing syndrome	2025-03-11	criteria provided, single submitter	clinical testing	The p.P192S variant (also known as c.574C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 574. The proline at codon 192 is replaced by serine, an amino acid with similar properties. This alteration was identified in conjunction with a second VHL alteration in a 9 year old patient with polycythemia. The variant was also present in the heterozygous state in the patient's unaffected father and brother (Pastore Y et al. Am. J. Hum. Genet., 2003 Aug;73:412-9). This alteration has also been reported in an individual with thyroid cancer diagnosed at age 67 (Lee B et al. Intern Med J, 2018 07;48:786-794). 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 available evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002490296	SCV002777881	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2024-02-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002322	SCV004206472	uncertain significance	Chuvash polycythemia	2023-10-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996075	SCV004841666	uncertain significance	Von Hippel-Lindau syndrome	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 192 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with renal cell carcinoma (PMID: 11536052, 24166983) and an individual affected with thyroid cancer (PMID: 26957611, 29607586). This variant also has been reported in trans with VHL p.Arg200Trp in an individual affected with recessive polycythemia (PMID: 12844285). Three different missense variants at this codon have been reported as likely disease-causing in ClinVar by an external laboratory (variation ID: 526677, 825946, 1488572), and p.Pro192Leu has been reported in two individuals affected with bilateral pheochromocytomas (PMID: 31397861). Grantham analysis predicts that p.Pro192Leu is a more disruptive substitution than the variant in question, p.Pro192Ser (PMID: 4843792). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996075	SCV004848883	uncertain significance	Von Hippel-Lindau syndrome	2023-01-23	criteria provided, single submitter	clinical testing	The p.Pro192Ser variant in VHL has been reported in one individuals with thyroid cancer (Lim 2016 PMID: 26957611). It has additionally been identified in trans with a pathogenic variant in a child with polycythemia; the p.Pro192Ser variant was identified in his father but it was not specified whether he exhibited a phenotype (Pastore 2003 PMID: 12844285). It was present in 0.002% of European chromosomes in the gnomAD database (https://gnomad.broadinstitute.org/). This variant has also been reported in ClinVar (Variation ID 2234). An additional variant at the same amino acid position, p.Pro192Thr has been identified (Variation ID 1488572). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
OMIM	RCV000002322	SCV000022480	pathogenic	Chuvash polycythemia	2003-02-15	no assertion criteria provided	literature only