VCV002429383.1 - ClinVar

NM_000553.6(WRN):c.600G>T (p.Trp200Cys)

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.

Likely pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000553.6(WRN):c.600G>T (p.Trp200Cys)

Variation ID: 2429383 Accession: VCV002429383.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p12 8: 31067128 (GRCh38) [ NCBI UCSC ] 8: 30924644 (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	Feb 18, 2023	Feb 18, 2023	Jan 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000553.6:c.600G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000544.2:p.Trp200Cys	missense
NC_000008.11:g.31067128G>T
NC_000008.10:g.30924644G>T
NG_008870.1:g.38867G>T
LRG_524:g.38867G>T
LRG_524t1:c.600G>T	LRG_524p1:p.Trp200Cys

... more HGVS ... less HGVS

Protein change

W200C

Other names

Canonical SPDI

NC_000008.11:31067127:G: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.

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.
WRN		-	-	GRCh38 GRCh37	3647	3804

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.
Progressive pulmonary failure	Likely pathogenic (1)	no assertion criteria provided	Jan 24, 2023	RCV003126320.2

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.
Likely pathogenic (Jan 24, 2023)	no assertion criteria provided Method: clinical testing	Progressive pulmonary failure (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Department of Medical Genetics, Gazi University Accession: SCV003035513.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (2) PubMed: 11863428‚ 36214313 Comment: The c.600G>T (p.Trp200Cys) variant in the NM_000553 transcript of the WRN gene, has not been reported in the literature, variant databases (ClinVar, LOVD), and population … (more) The c.600G>T (p.Trp200Cys) variant in the NM_000553 transcript of the WRN gene, has not been reported in the literature, variant databases (ClinVar, LOVD), and population database (GnomAD). The amino acid residue, p.Trp200, located in the exonuclease domain of the WRN protein, was conserved in vertebrates with the surrounding sequence according to the multiple sequence alignment analysis. In the 3-dimensional (3D) modeling of the exonuclease domain by the pdb file of 2FC0, the spatial position of Trp200 residue was observed to be close enough to interact with Glu84, which has been shown to be a critical residue for the enzymatic function (PMID: 11863428). It was also observed that the replacement of Trp with the Cys residue at position 200 demonstrated the altered interaction. With the Interaction Energy Matrix tool, it was calculated that Trp200 residue could interact with Glu84 through hydrophobic bonds with an energy level of -20.37 kJ/mol, which was the lowest value in the calculations among each amino acid-amino acid interaction of the exonuclease domain. The ΔΔG value of 1.66 kcal/mol calculated for the p.Trp200Cys mutation by the PremPS tool indicated the impaired protein stability owing to the mutation. As a result, it can be expected that the p.Trp200Cys variant would negatively affect the stability of the protein, causing disruption in the exonuclease activity of the WRN protein. (less) Number of individuals with the variant: 4 Clinical Features: Cough (present) , Dyspnea (present) , Spontaneous pneumothorax (present) , Respiratory insufficiency (present) , Cachexia (present) , Abnormal pulmonary interstitial morphology (present) Sex: male

Comment:

The c.600G>T (p.Trp200Cys) variant in the NM_000553 transcript of the WRN gene, has not been reported in the literature, variant databases (ClinVar, LOVD), and population database (GnomAD). The amino acid residue, p.Trp200, located in the exonuclease domain of the WRN protein, was conserved in vertebrates with the surrounding sequence according to the multiple sequence alignment analysis. In the 3-dimensional (3D) modeling of the exonuclease domain by the pdb file of 2FC0, the spatial position of Trp200 residue was observed to be close enough to interact with Glu84, which has been shown to be a critical residue for the enzymatic function (PMID: 11863428). It was also observed that the replacement of Trp with the Cys residue at position 200 demonstrated the altered interaction. With the Interaction Energy Matrix tool, it was calculated that Trp200 residue could interact with Glu84 through hydrophobic bonds with an energy level of -20.37 kJ/mol, which was the lowest value in the calculations among each amino acid-amino acid interaction of the exonuclease domain. The ΔΔG value of 1.66 kcal/mol calculated for the p.Trp200Cys mutation by the PremPS tool indicated the impaired protein stability owing to the mutation. As a result, it can be expected that the p.Trp200Cys variant would negatively affect the stability of the protein, causing disruption in the exonuclease activity of the WRN protein.

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
A homozygous missense variant in the WRN gene segregating in a family with progressive pulmonary failure with recurrent spontaneous pneumothorax and interstitial lung disease.	Sezer A	American journal of medical genetics. Part A	2023	PMID: 36214313
A minimal exonuclease domain of WRN forms a hexamer on DNA and possesses both 3'- 5' exonuclease and 5'-protruding strand endonuclease activities.	Xue Y	Biochemistry	2002	PMID: 11863428

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000553.6(WRN):c.600G>T (p.Trp200Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...