Submissions for variant NM_000551.4(VHL):c.449A>G (p.Asn150Ser)

dbSNP: rs760184234

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410629	SCV000489424	uncertain significance	Von Hippel-Lindau syndrome	2016-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000483327	SCV000568594	uncertain significance	not provided	2019-06-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26894854, 25586603)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534480	SCV000626906	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 150 of the VHL protein (p.Asn150Ser). This variant is present in population databases (rs760184234, gnomAD 0.0009%). This missense change has been observed in individual(s) with polycythemia (PMID: 25586603). This variant is also known as c.662A>G. ClinVar contains an entry for this variant (Variation ID: 371992). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000410629	SCV000897827	uncertain significance	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000483327	SCV001249722	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002328898	SCV002635396	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing	The p.N150S variant (also known as c.449A>G), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 449. The asparagine at codon 150 is replaced by serine, an amino acid with highly similar properties. This variant has been detected in conjunction with a VHL pathogenic variant in an individual with polycythemia (Sidhu A et al. Pediatr Blood Cancer, 2015 Jun;62:1113-4). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114530	SCV003800826	uncertain significance	not specified	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: VHL c.449A>G (p.Asn150Ser) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.449A>G also known as c.662A>G has been reported in the literature in an individual affected with polycythemia (Sidhu_2015) . These report(s) do not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003114530	SCV004024881	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463812	SCV004206470	uncertain significance	Chuvash polycythemia	2023-10-09	criteria provided, single submitter	clinical testing