Submissions for variant NM_000551.4(VHL):c.123_137dup (p.38SGPEE[3])

dbSNP: rs863224839

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000541671	SCV000626880	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-09-28	criteria provided, single submitter	clinical testing	This variant, c.123_137dup, results in the insertion of 5 amino acid(s) of the VHL protein (p.Ser43_Glu47dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 456571). 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.
Ambry Genetics	RCV000574163	SCV000675809	likely benign	Hereditary cancer-predisposing syndrome	2021-06-22	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.
GeneDx	RCV001576430	SCV001803618	likely benign	not provided	2021-02-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003459185	SCV004206460	uncertain significance	Chuvash polycythemia	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003773	SCV004825495	uncertain significance	Von Hippel-Lindau syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This variant causes a tandem duplication of 5 amino acids (p.Ser43_Glu47) in the VHL protein. This duplication is found at the N-terminus of the protein that is not conserved (PMID: 21386872), and functional studies have indicated that the first 53 a.a. at the N-terminus may be dispensable for VHL function (PMID: 9671762, 9751722, 10102622). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with paraganglioma (glomus caroticum tumor) (PMID: 34439371). This variant has been identified in 3/150148 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.