rs1060503557

Variant names:

• chr3-10141848-A-G
• rs1060503557
• NM_000551.4:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-10141848-A-G
• chr3-10141848-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000551.4(VHL):​c.1A>G​(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 0.000000723 in 1,383,702 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: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VHL NM_000551.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: -0.139
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 54 codons. Genomic position: 10142007. Lost 0.249 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10141848-A-G is Pathogenic according to our data. Variant chr3-10141848-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548790.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.71A>G		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.1A>G	p.Met1?	start_lost	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383702 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 681222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30822

American (AMR) AF: 0.00 AC: 0 AN: 33696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24498

East Asian (EAS) AF: 0.00 AC: 0 AN: 35338

South Asian (SAS) AF: 0.00 AC: 0 AN: 77990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1072328

Other (OTH) AF: 0.00 AC: 0 AN: 57126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 28, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease but an alternate initiation codon at Met45 could serve as an in-frame site (Iliopulos et al., 1998; Schoenfeld et al., 1998; Blankenship et al., 1999); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27845047, 33087929, 9751722, 9671762, 10102622) -

Von Hippel-Lindau syndrome Uncertain:1

Sep 06, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 548790). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the VHL gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, however there is an in-frame methionine 54 amino acids downstream which is reported to result in a biologically active isoform known as VHL19 (Iliopoulos O et al. Proc Natl Acad Sci USA.1998 Sep; 95(20):11661-6; Schoenfeld A et al. Proc Natl Acad Sci USA. 1998 Jul; 95(15):8817-22). This amino acid position is well conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	9.4
DANN	Benign	0.66
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.51	T
PhyloP100		-0.14
PROVEAN	Benign	-0.39	N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.060	T;D
Polyphen		0.0	B;B
Vest4		0.23
MutPred		0.99		Gain of MoRF binding (P = 0.2114);Gain of MoRF binding (P = 0.2114);
MVP		0.85
ClinPred		0.74	D
GERP RS		0.76
PromoterAI		-0.081	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.37
gMVP		0.54
Mutation Taster		=102/98	polymorphism

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

Other links and lift over

dbSNP: rs1060503557; hg19: chr3-10183532; COSMIC: COSV56555214;