NM_000551.4:c.74C>T

Variant names:

• chr3-10141921-C-T
• rs35460768
• NM_000551.4:c.74C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.74C>T (p.Pro25Leu) in VHL is a missense variant occurring prior to the second start site. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.005329 (6211/1141350 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020538/MONDO:0008667/078

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (20 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:28 O:1
• Conservation: PhyloP100: -0.0370
• Publications: 43 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• 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: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.74C>T	p.Pro25Leu	missense	Exon 1 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.74C>T	p.Pro25Leu	missense	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.74C>T	p.Pro25Leu	missense	Exon 1 of 2	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.74C>T	p.Pro25Leu	missense	Exon 1 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.74C>T	p.Pro25Leu	missense	Exon 1 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.120C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00303 AC: 439 AN: 144690 AF XY: 0.00294

Gnomad AFR exome AF: 0.000512

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000812

Gnomad NFE exome AF: 0.00514

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00471 AC: 6537 AN: 1387200 Hom.: 20 Cov.: 32 AF XY: 0.00460 AC XY: 3142 AN XY: 682572

African (AFR) AF: 0.000739 AC: 23 AN: 31132

American (AMR) AF: 0.000946 AC: 33 AN: 34898

Ashkenazi Jewish (ASJ) AF: 0.00799 AC: 197 AN: 24668

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35520

South Asian (SAS) AF: 0.00159 AC: 124 AN: 77890

European-Finnish (FIN) AF: 0.000933 AC: 45 AN: 48228

Middle Eastern (MID) AF: 0.000473 AC: 2 AN: 4224

European-Non Finnish (NFE) AF: 0.00550 AC: 5907 AN: 1073326

Other (OTH) AF: 0.00358 AC: 205 AN: 57314

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74490

African (AFR) AF: 0.000721 AC: 30 AN: 41594

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00269

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.00366 AC: 28

ExAC AF: 0.00161 AC: 143

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	7	not provided (7)
-	-	7	Von Hippel-Lindau syndrome (7)
-	-	3	Hereditary cancer-predisposing syndrome (3)
1	-	-	Maffucci syndrome (1)
-	-	1	Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma (1)
-	-	1	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.037
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.92
MPC		0.83
ClinPred		0.076	T
GERP RS		2.5
PromoterAI		0.028	Neutral
Varity_R		0.11
gMVP		0.50
Mutation Taster		=99/1	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: rs35460768; hg19: chr3-10183605; COSMIC: COSV56547511; COSMIC: COSV56547511;