VCV000411970.42 - ClinVar

NM_000551.4(VHL):c.373C>T (p.His125Tyr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(7); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000551.4(VHL):c.373C>T (p.His125Tyr)

Variation ID: 411970 Accession: VCV000411970.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 10146546 (GRCh38) [ NCBI UCSC ] 3: 10188230 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 29, 2017	Oct 20, 2024	Jun 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000551.4:c.373C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000542.1:p.His125Tyr	missense
NM_001354723.2:c.*18-3241C>T		intron variant
NM_198156.3:c.341-3241C>T		intron variant
NC_000003.12:g.10146546C>T
NC_000003.11:g.10188230C>T
NG_008212.3:g.9912C>T
NG_046756.1:g.4308C>T
LRG_322:g.9912C>T
LRG_322t1:c.373C>T	LRG_322p1:p.His125Tyr

... more HGVS ... less HGVS

Protein change

H125Y

Other names

Canonical SPDI

NC_000003.12:10146545:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA040676 dbSNP: rs375401722 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
VHL		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	835	2007
LOC107303340	-	-	-	GRCh38	-	1117

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 19, 2022	RCV000479517.26
Chuvash polycythemia Von Hippel-Lindau syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 3, 2022	RCV000462284.9
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 6, 2020	RCV000708764.5
Chuvash polycythemia Nonpapillary renal cell carcinoma Pheochromocytoma Von Hippel-Lindau syndrome	Uncertain significance (1)	criteria provided, single submitter	May 11, 2022	RCV002489086.2
Von Hippel-Lindau syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 8, 2023	RCV002272247.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000822211.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Uncertain significance (Jul 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Von Hippel-Lindau syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556948.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022
Uncertain significance (Oct 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Von Hippel-Lindau syndrome Chuvash polycythemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000553399.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 28492532‚ 31159747 Comment: This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 125 of the VHL protein (p.His125Tyr). … (more) This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 125 of the VHL protein (p.His125Tyr). This variant is present in population databases (rs375401722, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 411970). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. (less)
Uncertain significance (Sep 19, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565759.6 First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with paraganglioma but no other features of von Hippel-Lindau disease, as well as in an individual with a personal/family history of cancer not otherwise specified (Persu et al., 2012; Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 24969085, 22566194) (less)
Likely benign (May 06, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002621774.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: 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 … (more) 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. (less)
Uncertain significance (Jul 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000892671.28 First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (May 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nonpapillary renal cell carcinoma Pheochromocytoma Von Hippel-Lindau syndrome Chuvash polycythemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002790478.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain Significance (Jun 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Von Hippel-Lindau syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004827760.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (1) PubMed: 22566194 Comment: This missense variant replaces histidine with tyrosine at codon 125 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces histidine with tyrosine at codon 125 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual diagnosed with a paraganglioma and no additional features suggestive of von Hippel-Lindau syndrome (PMID: 22566194). This variant has been identified in 3/251494 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. (less) Number of individuals with the variant: 1 Zygosity: Single Heterozygote

Comment:

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 125 of the VHL protein (p.His125Tyr). This variant is present in population databases (rs375401722, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 411970). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with paraganglioma but no other features of von Hippel-Lindau disease, as well as in an individual with a personal/family history of cancer not otherwise specified (Persu et al., 2012; Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 24969085, 22566194)

Comment:

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.

Comment:

This missense variant replaces histidine with tyrosine at codon 125 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual diagnosed with a paraganglioma and no additional features suggestive of von Hippel-Lindau syndrome (PMID: 22566194). This variant has been identified in 3/251494 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Prevalence and spectrum of SDHx mutations in pheochromocytoma and paraganglioma in patients from Belgium: an update.	Persu A	Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme	2012	PMID: 22566194

Text-mined citations for rs375401722 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000551.4(VHL):c.373C>T (p.His125Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375401722 ...