rs578091032

chr3-10141850-G-Achr3-10141850-G-Cchr3-10141850-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>A(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 0.0000567 in 1,535,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: VHL NM_000551.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1 O:1
• Conservation: PhyloP100: 0.0460

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 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	UniProt
VHL	NM_000551.4	c.3G>A	p.Met1?	start_lost	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.3G>A	p.Met1?	start_lost	1/3
VHL	NM_198156.3	c.3G>A	p.Met1?	start_lost	1/2
VHL	NR_176335.1	n.73G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.3G>A	p.Met1?	start_lost	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000647 AC: 9 AN: 139020 Hom.: 0 AF XY: 0.0000404 AC XY: 3 AN XY: 74312

Gnomad AFR exome AF: 0.000415

Gnomad AMR exome AF: 0.0000439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000588

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.0000506 AC: 70 AN: 1383052 Hom.: 0 Cov.: 32 AF XY: 0.0000602 AC XY: 41 AN XY: 680752

Gnomad4 AFR exome AF: 0.0000648

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000424

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000448

Gnomad4 OTH exome AF: 0.0000701

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74508

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000982

ExAC AF: 0.0000447 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Von Hippel-Lindau syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant results in the loss of the translation initiator methionine at codon 1 of the VHL protein. However, VHL encodes a smaller protein isoform from internal translation initiation at methionine 54 (PMID: 9671762, 10102622). Functional studies have reported that the smaller protein isoform can rescue VHL functions in renal carcinoma cells lacking endogenous VHL expression (PMID: 9671762, 9751722, 10102622) and a mouse model for VHL start codon loss found that most VHL functions are intact (PMID: 23541568). This variant has been reported in an individual affected with sporadic renal cell carcinoma along with a second VHL variant, p.Met211Leu, who lacks other manifestations or family history of von Hippel-Lindau syndrome (PMID: 31034483). This variant has been identified in 12/170382 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 11, 2019	This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: No criteria apply. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 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 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 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 0.04%). Disruption of the initiator codon has been observed in individual(s) with renal carcinoma (PMID: 31034483). ClinVar contains an entry for this variant (Variation ID: 135406). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 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 isolated clear cell renal cell carcinoma (Christensen et al., 2019); Published functional studies demonstrate normal regulation of HIF1a and aberrant microtubule dynamics in cells derived from a mouse model homozygous for this variant; however the homozygous mice do not have an increased rate of VHL-related tumors or disease (Frew et al., 2013); This variant is associated with the following publications: (PMID: 24728327, 11505222, 20151405, 10102622, 9751722, 13679920, 26224408, 12510195, 26211615, 29018234, 28580172, 28425505, 9671762, 35735610, 31034483, 23541568) -

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

Apr 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	14
Dann	Benign	0.90
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.65	D;D
PROVEAN	Benign	-0.46	N;N
REVEL	Uncertain	0.38
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		0.21	T
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

Other links and lift over

dbSNP: rs578091032; hg19: chr3-10183534; COSMIC: COSV56542939; COSMIC: COSV56542939;