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

dbSNP: rs578091032

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409700	SCV000489077	uncertain significance	Von Hippel-Lindau syndrome	2016-08-23	criteria provided, single submitter	clinical testing
Invitae	RCV000467198	SCV000553375	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-30	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 0.04%). Disruption of the initiator codon has been observed in individual(s) with renal carcinoma (PMID: 31034483). ClinVar contains an entry for this variant (Variation ID: 135406). 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	RCV000657025	SCV000566718	uncertain significance	not provided	2023-04-28	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 isolated clear cell renal cell carcinoma (Christensen et al., 2019); Published functional studies demonstrate normal regulation of HIF1a and aberrant microtubule dynamics in cells derived from a mouse model homozygous for this variant; however the homozygous mice do not have an increased rate of VHL-related tumors or disease (Frew et al., 2013); This variant is associated with the following publications: (PMID: 24728327, 11505222, 20151405, 10102622, 9751722, 13679920, 26224408, 12510195, 26211615, 29018234, 28580172, 28425505, 9671762, 35735610, 31034483, 23541568)
Ambry Genetics	RCV000492595	SCV000580981	likely benign	Hereditary cancer-predisposing syndrome	2022-10-27	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.
Illumina Laboratory Services, Illumina	RCV000409700	SCV001309436	uncertain significance	Von Hippel-Lindau syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000409700	SCV001369690	uncertain significance	Von Hippel-Lindau syndrome	2019-12-11	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: No criteria apply.
Sema4, Sema4	RCV000492595	SCV002534171	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122260	SCV002760265	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483231	SCV002785187	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2022-04-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000409700	SCV004841627	uncertain significance	Von Hippel-Lindau syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation initiator methionine at codon 1 of the VHL protein. However, VHL encodes a smaller protein isoform from internal translation initiation at methionine 54 (PMID: 9671762, 10102622). Functional studies have reported that the smaller protein isoform can rescue VHL functions in renal carcinoma cells lacking endogenous VHL expression (PMID: 9671762, 9751722, 10102622) and a mouse model for VHL start codon loss found that most VHL functions are intact (PMID: 23541568). This variant has been reported in an individual affected with sporadic renal cell carcinoma along with a second VHL variant, p.Met211Leu, who lacks other manifestations or family history of von Hippel-Lindau syndrome (PMID: 31034483). This variant has been identified in 12/170382 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.
ITMI	RCV000122260	SCV000086485	not provided	not specified	2013-09-19	no assertion provided	reference population