Submissions for variant NM_000551.4(VHL):c.123_137del (p.38SGPEE[1])

dbSNP: rs863224839

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197814	SCV000255297	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This variant, c.123_137del, results in the deletion of 5 amino acid(s) of the VHL protein (p.Ser43_Glu47del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758049121, gnomAD 0.03%). This variant has been observed in individual(s) with von Hippel-Lindau (VHL) disease (PMID: 15300849, 37937776). ClinVar contains an entry for this variant (Variation ID: 216870). 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	RCV000222096	SCV000276096	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	The c.123_137del15 variant (also known as p.E43_P47del) is located in coding exon 1 of the VHL gene. This variant results from an in-frame AGAGTCCGGCCCGGA deletion at nucleotide positions 123 to 137. This results in the in-frame deletion of codons 43 through 47. This alteration has been previously identified in an individual from the French VHL Registry (Gallou C, et al. Hum. Mutat. 2004 Sep;24(3):215-24). However, there is an alternate in-frame methionine 54 amino acids from the primary initiation site in VHL which is reported to result in a biologically active isoform known as VHL19 (Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6. Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22). The amino acids impacted by the c.123_137del15 alteration are located 5' of this alternative initiation codon and as such their significance is unclear. 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.
GeneDx	RCV000255039	SCV000322352	likely benign	not provided	2021-03-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15300849)
Mendelics	RCV000987110	SCV001136308	uncertain significance	Von Hippel-Lindau syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000987110	SCV005404867	likely benign	Von Hippel-Lindau syndrome	2024-08-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Fulgent Genetics, Fulgent Genetics	RCV005031751	SCV005658790	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2024-06-21	criteria provided, single submitter	clinical testing