Submissions for variant NM_000551.4(VHL):c.1A>G (p.Met1Val)

dbSNP: rs1060503557

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000662755	SCV000785543	uncertain significance	Von Hippel-Lindau syndrome	2017-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV001230391	SCV001402868	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the VHL mRNA. The next in-frame methionine is located at codon 54. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 548790). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). 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.
Revvity Omics, Revvity	RCV001784228	SCV002024783	likely pathogenic	not provided	2019-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002422448	SCV002717791	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-23	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the VHL gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, however there is an in-frame methionine 54 amino acids downstream which is reported to result in a biologically active isoform known as VHL19 (Iliopoulos O et al. Proc Natl Acad Sci USA.1998 Sep; 95(20):11661-6; Schoenfeld A et al. Proc Natl Acad Sci USA. 1998 Jul; 95(15):8817-22). This amino acid position is well conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001784228	SCV004040170	uncertain significance	not provided	2023-03-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease but an alternate initiation codon at Met45 could serve as an in-frame site (Iliopulos et al., 1998; Schoenfeld et al., 1998; Blankenship et al., 1999); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27845047, 33087929, 9751722, 9671762, 10102622)