Submissions for variant NM_000551.4(VHL):c.392A>G (p.Asn131Ser)

dbSNP: rs1553619963

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590750	SCV000697509	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-09	criteria provided, single submitter	clinical testing	Variant summary: VHL c.392A>G variant affects a conserved nucleotide, resulting in an amino acid change from Asn to Ser at codon 131 in beta domain of the protein. 2/4 in-silico tools predict this variant to be damaging. Other mutations including missense mutations at residue 131 (such as N131T, N131K, N131Y, N131X, N131fsX3, etc.) have been reported in patients affected with VHL disease, suggesting that the codon 131 is likely to be a hot-spot for mutation. This variant has been reported in two Japanese VHL families (Yoshida_2000, Imanaka_2006); two affected brothers were shown to carry the variant in one family suggesting the cosegregation of the variant in the family. The variant was not found in approximately 121412 control chromosomes from the large and diverse ExAC cohorts. Taken together, this variant is currently classified as a Probable Disease Variant (or Likely Pathogenic).
GeneDx	RCV002225684	SCV002504189	likely pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	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 c.605A>G, p.N202S, p.N172S; This variant is associated with the following publications: (PMID: 19955664, 10761708, 19309509, 17001110, 27527340)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530908	SCV003525040	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2021-12-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn131 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 17001110, 21384277; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 496062). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 17001110; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 131 of the VHL protein (p.Asn131Ser).