Submissions for variant NM_000551.4(VHL):c.99_113dup (p.Ala35_Gly39dup)

dbSNP: rs1236159514

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001062374	SCV001227170	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This variant, c.99_113dup, results in the insertion of 5 amino acid(s) of the VHL protein (p.Ala35_Gly39dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 856826). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV001575478	SCV001802482	uncertain significance	not provided	2019-11-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In-frame insertion of 5 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002379585	SCV002694582	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-08	criteria provided, single submitter	clinical testing	The c.99_113dup15 variant (also known as p.A35_G39dup), located in coding exon 1 of the VHL gene, results from an in-frame duplication of 15 nucleotides at nucleotide positions 99 to 113. This results in the duplication of 5 extra residues (AEESG) between codons 35 and 39. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003462593	SCV004208765	uncertain significance	Chuvash polycythemia	2023-07-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000126	SCV004825138	uncertain significance	Von Hippel-Lindau syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of five amino acids in the VHL protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 2/145164 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.