VCV002500119.1 - ClinVar

NM_019841.7(TRPV5):c.1792G>A (p.Val598Met)

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.

(1)

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.

Pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_019841.7(TRPV5):c.1792G>A (p.Val598Met)

Variation ID: 2500119 Accession: VCV002500119.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q34 7: 142909593 (GRCh38) [ NCBI UCSC ] 7: 142606759 (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	Oct 7, 2023	Oct 7, 2023	Apr 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_019841.7:c.1792G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_062815.3:p.Val598Met	missense
NC_000007.14:g.142909593C>T
NC_000007.13:g.142606759C>T
NG_046912.1:g.29131G>A

Protein change

V598M

Other names

Canonical SPDI

NC_000007.14:142909592:C:T

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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.

Links

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.
TRPV5		-	-	GRCh38 GRCh38 GRCh37	58	107

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.
Renal Calcium Wasting Hypercalciuria	Pathogenic (1)	no assertion criteria provided	Apr 4, 2023	RCV003332422.1

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.
Pathogenic (Apr 04, 2023)	no assertion criteria provided Method: research, in vitro	Renal Calcium Wasting Hypercalciuria (Autosomal recessive inheritance) Affected status: no, not applicable, yes Allele origin: germline, not applicable	Gene Mapping Laboratory, Hacettepe University Accession: SCV003852754.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: The p.Val598Met variant is found in a family of 8 with 3 affected individuals (each has hypercalciuria). The variant is heterozygous in only 4 individuals … (more) The p.Val598Met variant is found in a family of 8 with 3 affected individuals (each has hypercalciuria). The variant is heterozygous in only 4 individuals in gnomAD and is not found in homozygosity in large population databases. Additional homozygosity mapping has excluded 98.85% of the genome for Identity-by-decent. Additional in vitro cell models show that cells transfected with p.Val598Met have lower calcium permeability and surface channel expression compared to cells transfected with the wild-type protein. The mutant protein also undergoes proteasomal degradation. (less) Observation 1: Number of individuals with the variant: 3 Clinical Features: Nephrolithiasis (absent) , Hypercalciuria (present) Age: 1-12 years Sex: mixed Ethnicity/Population group: Middle-Eastern Geographic origin: Syria Comment on evidence: All 3 homozygous individuals have increased renal excretion of calcium at a young age. Observation 2: Clinical Features: Nephrolithiasis (present) , Hypercalciuria (absent) Age: 20-29 years Sex: female Ethnicity/Population group: Middle-Eastern Geographic origin: Syria Observation 3: Clinical Features: Nephrolithiasis (absent) , Hypercalciuria (absent) Age: 0-9 years Sex: female Ethnicity/Population group: Middle Eastern Geographic origin: Syria Observation 4: Clinical Features: Nephrolithiasis (absent) , Hypercalciuria (absent) Age: 30-39 years Sex: male Ethnicity/Population group: Middle Eastern Geographic origin: Syria Observation 5: Clinical Features: Nephrolithiasis (absent) , Hypercalciuria (absent) Age: 0-9 years Sex: female Ethnicity/Population group: Middle Eastern Geographic origin: Syria Observation 6: Method: HEK293 cells were transfected with plasmids encoding either the wild-type channel or the p.Val598Met variant. The Ca permeability of the cells was evaluated by measuring the radioactive Ca-45 uptake via a scintillation counter. TRPV5 protein semi-quantification was carried out using SDS-PAGE and glycosylation variants were identified by their different molecular weights. A cell surface biotinylation assay using EZ-link Sulfo-NHS-LC-LC biotin was used for measuring surface expression. Experiments were repeated to demonstrate proteasomal degradation by adding an inhibitor of this pathway, MG-132. Result: The calcium permeability of HEK293 cells transfected with the p.Val598Met channel is lower compared to the wild-type channel. Additionally, the surface expression of the mutant channel is lower, its glycosylation is defective, and it is targeted for proteasomal degradation.

Comment:

The p.Val598Met variant is found in a family of 8 with 3 affected individuals (each has hypercalciuria). The variant is heterozygous in only 4 individuals in gnomAD and is not found in homozygosity in large population databases. Additional homozygosity mapping has excluded 98.85% of the genome for Identity-by-decent. Additional in vitro cell models show that cells transfected with p.Val598Met have lower calcium permeability and surface channel expression compared to cells transfected with the wild-type protein. The mutant protein also undergoes proteasomal degradation.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)	Method not provided Method not provided Method not provided Method not provided Method not provided HEK293 cells were transfected with plasmids encoding either the wild-type channel or the p.Val598Met variant. The Ca permeability of the cells was evaluated by measuring the radioactive Ca-45 uptake via a scintillation counter. TRPV5 protein semi-quantification was carried out using SDS-PAGE and glycosylation variants were identified by their different molecular weights. A cell surface biotinylation assay using EZ-link Sulfo-NHS-LC-LC biotin was used for measuring surface expression. Experiments were repeated to demonstrate proteasomal degradation by adding an inhibitor of this pathway, MG-132.	Result not provided Result not provided Result not provided Result not provided Result not provided The calcium permeability of HEK293 cells transfected with the p.Val598Met channel is lower compared to the wild-type channel. Additionally, the surface expression of the mutant channel is lower, its glycosylation is defective, and it is targeted for proteasomal degradation.	Gene Mapping Laboratory, Hacettepe University Accession: SCV003852754.1

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 07, 2023

ClinVar Genomic variation as it relates to human health

NM_019841.7(TRPV5):c.1792G>A (p.Val598Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...