VCV000008786.11 - ClinVar

NM_005591.4(MRE11):c.630G>C (p.Trp210Cys)

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.

(7)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005591.4(MRE11):c.630G>C (p.Trp210Cys)

Variation ID: 8786 Accession: VCV000008786.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q21 11: 94476318 (GRCh38) [ NCBI UCSC ] 11: 94209484 (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 14, 2016	Sep 16, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005591.4:c.630G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005582.1:p.Trp210Cys	missense
NM_001330347.2:c.630G>C	NP_001317276.1:p.Trp210Cys	missense
NM_005590.4:c.630G>C	NP_005581.2:p.Trp210Cys	missense
NC_000011.10:g.94476318C>G
NC_000011.9:g.94209484C>G
NG_007261.1:g.22557G>C
LRG_85:g.22557G>C
LRG_85t1:c.630G>C	LRG_85p1:p.Trp210Cys

... more HGVS ... less HGVS

Protein change

W210C

Other names

Canonical SPDI

NC_000011.10:94476317:C:G

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

ClinGen: CA119930 OMIM: 600814.0005 dbSNP: rs137852763 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.
MRE11		-	-	GRCh38 GRCh37	2145	2181

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.
Ataxia-telangiectasia-like disorder 1	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000009331.14
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 2, 2024	RCV000712327.4

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 (Jun 30, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000842797.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (7) PubMed: 15574463‚ 18652530‚ 21324166‚ 27124789‚ 23080121‚ 22705791‚ 22078559
Likely pathogenic (Sep 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia-like disorder 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023515.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia-like disorder 1 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520878.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Ataxia-telangiectasia-like disorder 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805146.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 02, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201979.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Published functional studies suggest the p.(W210C) variant results in slightly lower nuclease activity, diminishes the interaction with Nbs1, and has similar sensitivity to DNA damage … (more) Published functional studies suggest the p.(W210C) variant results in slightly lower nuclease activity, diminishes the interaction with Nbs1, and has similar sensitivity to DNA damage when compared to wildtype (PMID: 22078559, 22705791, 23080121, 23388631); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35048780, 31908056, 18652530, 15574463, 22705791, 31033087, 37808486, 23388631, 21324166, 22078559, 23080121, 32668560, 27124789, 17674145, 21035407, 18568480, 16189143, 31130284, 18083591) (less)
Pathogenic (Sep 26, 2019)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia-like disorder 1 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001133231.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020
Pathogenic (Jan 15, 2005)	no assertion criteria provided Method: literature only	ATAXIA-TELANGIECTASIA-LIKE DISORDER 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029549.4 First in ClinVar: Apr 04, 2013 Last updated: Jan 16, 2020	Publications: PubMed (1) PubMed: 15574463 Comment on evidence: In 10 patients from 3 unrelated Saudi Arabian families with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391), Fernet et al. (2005) identified homozygosity for a 630G-C transversion in … (more) In 10 patients from 3 unrelated Saudi Arabian families with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391), Fernet et al. (2005) identified homozygosity for a 630G-C transversion in exon 7 of the MRE11A gene, resulting in a trp210-to-cys (W210C) substitution between motifs III and IV of the N-terminal nuclease domain. Patients presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest 37-year-old patient. Extraneurologic features, such as telangiectasia, raised alpha-fetoprotein, and reduced immunoglobulin levels, were absent. (less)

Comment:

Published functional studies suggest the p.(W210C) variant results in slightly lower nuclease activity, diminishes the interaction with Nbs1, and has similar sensitivity to DNA damage when compared to wildtype (PMID: 22078559, 22705791, 23080121, 23388631); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35048780, 31908056, 18652530, 15574463, 22705791, 31033087, 37808486, 23388631, 21324166, 22078559, 23080121, 32668560, 27124789, 17674145, 21035407, 18568480, 16189143, 31130284, 18083591)

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
Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden.	Abouelhoda M	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 27124789
Mre11 ATLD17/18 mutation retains Tel1/ATM activity but blocks DNA double-strand break repair.	Limbo O	Nucleic acids research	2012	PMID: 23080121
Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling.	Schiller CB	Nature structural & molecular biology	2012	PMID: 22705791
Crystal structure of human Mre11: understanding tumorigenic mutations.	Park YB	Structure (London, England : 1993)	2011	PMID: 22078559
Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia.	Bohlega SA	BMC medical genetics	2011	PMID: 21324166
Assessment of carriers' frequency of a novel MRE11 mutation responsible for the rare ataxia telangiectasia-like disorder.	Alsbeih G	Genetic testing	2008	PMID: 18652530
Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder.	Fernet M	Human molecular genetics	2005	PMID: 15574463

Text-mined citations for rs137852763 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005591.4(MRE11):c.630G>C (p.Trp210Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852763 ...