Submissions for variant NM_000551.4(VHL):c.610G>T (p.Glu204Ter)

dbSNP: rs758853661

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV004691262	SCV005187300	uncertain significance	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	The variant NM_000551.4(VHL):c.610G>T (p.Glu204Ter) is a truncating variant predicted to cause a premature stop codon in biologically-relevant-exon (the third exon). This is not predicted to lead to nonsense mediated decay, although in VHL a loss-of-function is an established disease mechanism. As the role of the region between amino acids (AA205 -213) is overall unknown, this receives PVS1_Moderate per the VHL VCEP PVS1 decision tree (PVS1_Moderate). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00000028 (2/1112000 from European, Non-Finnish Population). PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD (PM2_Supporting). A total of 4 cases between three commercial laboratories did not identify any cases with VHL spectrum tumors, and one case is >= 60yo without VHL spectrum tumors. PS4 is not met, and BS2 is not met. There are no additional reports identified in the literature. In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631268	SCV000752296	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2019-12-19	criteria provided, single submitter	clinical testing	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. This variant is expected to delete a portion of the C-terminal region of the VHL protein near the β domain (a-helix) (PMID: 14691445, 14987375). Experimental studies are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant has not been reported in the literature in individuals with VHL-related disease. This variant is present in population databases (rs758853661, ExAC 0.009%). This sequence change results in a premature translational stop signal in the VHL gene (p.Glu204*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 10 amino acids of the VHL protein.
Ambry Genetics	RCV002358758	SCV002660520	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-04	criteria provided, single submitter	clinical testing	The p.E204* variant (also known as c.610G>T), located in coding exon 3 of the VHL gene, results from a G to T substitution at nucleotide position 610. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of VHL gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 10 amino acids of the protein. The exact functional effect of this alteration is unknown. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.