3-10141850-G-C

Variant names:

• chr3-10141850-G-C
• rs578091032
• NM_000551.4:c.3G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1_Strong PS1_Moderate PM2 BP6

The NM_000551.4(VHL):​c.3G>C​(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 1,383,052 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 U:2 B: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 7 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 159 CDS bases. Genomic position: 10142006. Lost 0.248 part of the original CDS.
• PS1: Another start lost variant in NM_000551.4 (VHL) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-10141850-G-C is Benign according to our data. Variant chr3-10141850-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582995.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.3G>C	p.Met1?	start_lost	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.3G>C	p.Met1?	start_lost	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.3G>C	p.Met1?	start_lost	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.73G>C		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.3G>C	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: 1383052 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 680752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Apr 05, 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). 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: 582995). 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

Jun 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.3G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 3. 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 in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Von Hippel-Lindau syndrome Benign:1

Aug 20, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Benign	0.79
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.64	T
PROVEAN	Benign	-0.46	N;N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	.;D
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		0.92	D
GERP RS		0.18
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;