Submissions for variant NM_000551.4(VHL):c.3G>T (p.Met1Ile)

dbSNP: rs578091032

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000228663	SCV000285495	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-02-01	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 present in population databases (rs578091032, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with breast cancer and/or pilocytic astrocytoma (PMID: 30093976, 33840814). ClinVar contains an entry for this variant (Variation ID: 238106). 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.
GeneDx	RCV000236708	SCV000293412	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform, pVHL19, that may result in a functional protein (Iliopoulos et al., 1998; Schoenfeld et al., 1998; Blankenship et al., 1999); Observed in an individual with early-onset breast cancer (Chan et al., 2018); This variant is associated with the following publications: (PMID: 9751722, 10102622, 9671762, 23541568, 30093976, 33840814, 32191290)
Counsyl	RCV000411808	SCV000488346	uncertain significance	Von Hippel-Lindau syndrome	2016-03-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562501	SCV000675801	likely benign	Hereditary cancer-predisposing syndrome	2022-08-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV000236708	SCV000805345	uncertain significance	not provided	2018-03-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562501	SCV002534172	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307459	SCV002600553	uncertain significance	not specified	2022-10-18	criteria provided, single submitter	clinical testing	Variant summary: VHL c.3G>T (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (Met52). The variant allele was found at a frequency of 5.8e-05 in 139020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3G>T has been reported in the literature in individuals affected with Breast cancer (Chan_2018). This report does 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 of this particular variant has been reported. There are, however, reports that a second conserved in-frame AUG acts as the start site for an alternate VHL product containing the functional domains in human cells, and knock-in mice that produce the shorter isoform appear phenotypically normal except for altered microtubule dynamics (Schoenfeld_1998, Iliopoulos_1998, Frew_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002487052	SCV002792281	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2021-11-24	criteria provided, single submitter	clinical testing