3-10141850-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_000551.4(VHL):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,535,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

VHL
NM_000551.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 0.0460

Variant links:

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]

VHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VHL	NM_000551.4 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/3	ENST00000256474.3
VHL	NM_001354723.2 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/3
VHL	NM_198156.3 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/2
VHL	NR_176335.1 linkuse as main transcript	n.73G>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/3	1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000575

AC:

AN:

139020

Hom.:

AF XY:

0.0000538

AC XY:

AN XY:

74312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000945

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000205

Gnomad NFE exome

AF:

0.0000588

Gnomad OTH exome

AF:

0.000250

GnomAD4 exome

AF:

0.0000448

AC:

AN:

1383052

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

680752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000890

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000848

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.000105

Gnomad4 NFE exome

AF:

0.0000401

Gnomad4 OTH exome

AF:

0.000123

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000447

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2023	Initiation codon variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform, pVHL19, that may result in a functional protein (Iliopoulos et al., 1998; Schoenfeld et al., 1998; Blankenship et al., 1999); Observed in an individual with early-onset breast cancer (Chan et al., 2018); This variant is associated with the following publications: (PMID: 9751722, 10102622, 9671762, 23541568, 30093976, 33840814, 32191290) -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 14, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 20, 2022	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 18, 2022

Variant summary: VHL c.3G>T (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (Met52). The variant allele was found at a frequency of 5.8e-05 in 139020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3G>T has been reported in the literature in individuals affected with Breast cancer (Chan_2018). This report does not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function of this particular variant has been reported. There are, however, reports that a second conserved in-frame AUG acts as the start site for an alternate VHL product containing the functional domains in human cells, and knock-in mice that produce the shorter isoform appear phenotypically normal except for altered microtubule dynamics (Schoenfeld_1998, Iliopoulos_1998, Frew_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Von Hippel-Lindau syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 08, 2016

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

This sequence change affects the initiator methionine of the VHL mRNA. The next in-frame methionine is located at codon 54. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. This variant is present in population databases (rs578091032, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with breast cancer and/or pilocytic astrocytoma (PMID: 30093976, 33840814). ClinVar contains an entry for this variant (Variation ID: 238106). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). 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. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Benign

-0.13

Cadd

Benign

Dann

Benign

0.80

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.63

MutationTaster

Benign

0.61

D;D

PROVEAN

Benign

-0.46

N;N

REVEL

Uncertain

0.37

Sift4G

Benign

0.25

T;T

Polyphen

0.0

B;B

Vest4

0.22

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0604);Gain of catalytic residue at M1 (P = 0.0604);

MVP

0.85

ClinPred

0.50

GERP RS

0.18

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.64

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over