rs730882031

Positions:

• chr3-10142038-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000256474.3(VHL):​c.192del​(p.Ser65ArgfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R64R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL ENST00000256474.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.732

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10142038-GC-G is Pathogenic according to our data. Variant chr3-10142038-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142038-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.192del	p.Ser65ArgfsTer2	frameshift_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.192del	p.Ser65ArgfsTer2	frameshift_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.192del	p.Ser65ArgfsTer2	frameshift_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.262del		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.192del	p.Ser65ArgfsTer2	frameshift_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 03, 2016

Variant summary: This c.192delC variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 65 and leads to a premature termination codon one amino acid downstream. It is predicted to cause a truncated or absent protein product. Mutation taster predicts this variant to be disease-causing. The variant was not observed in the large and broad cohorts of the ExAC project or ESP. The variant of interest has been detected in RCC tumor samples (Shuin_1994 and Suzuki_1997). Truncations downstream of this position have been classified as disease variants by our laboratory (Such as c.214delT and C.230delG). One clinical lab (via ClinVar) classified this variant as pathogenic. Considering all, this variant has been classified as Likely Pathogenic until additional information becomes available. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2014

The c.192delC mutation in the VHL gene has been reported previously in association with von Hippel-Lindau Syndrome (Suzuki et al., 1997; Shuin et al., 1994). The deletion causes a frameshift starting with codon Serine 65, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ser65ArgfsX2. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay This mutation may also be referred to as p.S136RfsX2 in the literature due to alternative numbering. The variant is found in VHL panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730882031; hg19: chr3-10183722; COSMIC: COSV56565831; COSMIC: COSV56565831;