rs1553619440

Variant names:

• chr3-10142125-G-A
• rs1553619440
• NM_000551.4:c.278G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10142125-G-A
• chr3-10142125-G-C
• chr3-10142125-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.278G>A​(p.Gly93Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.47

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.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142124-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-10142125-G-A is Pathogenic according to our data. Variant chr3-10142125-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.278G>A	p.Gly93Asp	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.278G>A	p.Gly93Asp	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.278G>A	p.Gly93Asp	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.348G>A		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.278G>A	p.Gly93Asp	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Aug 01, 2018

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.278G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Asp. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 101892 control chromosomes. This variant has been reported in multiple VHL pts and classified as pathgenic by literatures. Variants G93R, G93C, and G93S are all listed as disease mutation in HGMD and have been reported in multiple literatures, suggesting the codon 93 is a hypermutable amino acid and a hotspot for mutations. Taken together, this variant was classified as a Pathogenic. -

not provided Pathogenic:2

Nov 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VHL c.278G>A (p.Gly93Asp) variant has been reported in the published literature in several individuals and families affected with von Hippel-Lindau (VHL) syndrome (PMIDs: 7728151 (1995), 10761708 (2000), 11114638 (2000), 22799452 (2012), 25078357 (2014), 28650583 (2017), 28721348 (2017)). Analysis of in vitro research on the effect of this variant on VHL function yielded inconclusive results (PMIDs: 14556007 (2003), 14973063 (2004)), further research is needed. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Aug 05, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with VHLS. Multiple missense variants at this codon, including at least one considered to be pathogenic or likely pathogenic, have been reported in individuals with VHLS and/or pheochromocytoma suggesting this variant may also cause disease. This variant is also referred to as c.491G>A; (p.Gly164Asp) in published literature. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 93 of the VHL protein (p.Gly93Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 16314641; Invitae). This variant is also known as c.491G>A (p.Gly164Asp). ClinVar contains an entry for this variant (Variation ID: 496054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 14556007, 14973063). This variant disrupts the p.Gly93 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 12000816; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.96		Loss of glycosylation at P97 (P = 0.0728);Loss of glycosylation at P97 (P = 0.0728);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.99

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: rs1553619440; hg19: chr3-10183809; COSMIC: COSV56560242; COSMIC: COSV56560242;