Four siblings from two unrelated kindreds died during infancy with markedly similar medical problems including severe pulmonary disease following viral pneumonia with evidence of combined T- and B-cell immunodeficiency. Chromosomal testing showed signs of increased aneuploidy/breakage. Cells from the subjects had increased sensitivity to DNA damage. One sib pair harbored rare (p.Leu264Phe) and novel (p.Pro209Leu) compound heterozygous missense variants in NSMCE3, while the other sib pair was homozygous for the p.Leu264Phe variant in NSMCE3.
ClinVar Genomic variation as it relates to human health
NM_138704.4(NSMCE3):c.790C>T (p.Leu264Phe)
Germline
Classification
Help
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.
(6)
Help
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_138704.4(NSMCE3):c.790C>T (p.Leu264Phe)
Variation ID: 267795 Accession: VCV000267795.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q13.1 15: 29268916 (GRCh38) [ NCBI UCSC ] 15: 29561120 (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 Nov 13, 2016 Jul 15, 2024 Apr 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015307.2:c.277-16438C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_138704.4:c.790C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619649.1:p.Leu264Phe missense NM_001387214.1:c.277-16438C>T intron variant NM_001387215.1:c.-12-16438C>T intron variant NM_001387216.1:c.-12-16438C>T intron variant NM_001387217.1:c.-12-16438C>T intron variant NC_000015.10:g.29268916G>A NC_000015.9:g.29561120G>A NG_053143.1:g.5914C>T - Protein change
- L264F
- Other names
-
NSMCE3, LEU264PHE (rs199905054)
- Canonical SPDI
- NC_000015.10:29268915:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ENTREP2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh37 |
50 | 376 | |
| NSMCE3 | - | - |
GRCh38 GRCh38 GRCh38 GRCh37 |
- | 325 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 17, 2016 | RCV000258542.1 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Apr 11, 2024 | RCV000412499.2 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Jan 7, 2024 | RCV001529172.9 |
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
(Mar 17, 2016)
|
criteria provided, single submitter
Method: research, in vitro, in vivo
|
Lung damage, immunodeficiency and chromosome breakage syndrome
Autosomal recessive syndrome due to
(more...)
(Autosomal recessive inheritance)
Affected status: no, yes, not applicable
Allele origin:
inherited,
unknown,
not applicable
|
Sharon E. Plon Laboratory, Baylor College of Medicine
Accession: SCV000266831.1
First in ClinVar: Nov 13, 2016 Last updated: Nov 13, 2016
Comment:
The researchers Drs. Sharon Plon and Giis van Haaften were connected through Genematcher (https://genematcher.org), a service that enables contact between clinicians & researchers working on … (more)
The researchers Drs. Sharon Plon and Giis van Haaften were connected through Genematcher (https://genematcher.org), a service that enables contact between clinicians & researchers working on genes. (less)
|
Comment:
Four siblings from two unrelated kindreds died during infancy with markedly similar medical problems including severe pulmonary disease following viral pneumonia with evidence of combined … (more)
Four siblings from two unrelated kindreds died during infancy with markedly similar medical problems including severe pulmonary disease following viral pneumonia with evidence of combined T- and B-cell immunodeficiency. Chromosomal testing showed signs of increased aneuploidy/breakage. Cells from the subjects had increased sensitivity to DNA damage. One sib pair harbored rare (p.Leu264Phe) and novel (p.Pro209Leu) compound heterozygous missense variants in NSMCE3, while the other sib pair was homozygous for the p.Leu264Phe variant in NSMCE3. (less)
Observation 1:
Family history: yes
Sex: female
Ethnicity/Population group: European Caucasoid
Geographic origin: Netherlands
Comment on evidence:
Approximate age at death: 12mo
Segregation observed: yes
Secondary finding: no
Observation 2:
Family history: yes
Sex: female
Ethnicity/Population group: European Caucasoid
Geographic origin: Netherlands
Comment on evidence:
Approximate age at death: 14 mo
Segregation observed: yes
Secondary finding: no
Observation 3:
Family history: yes
Sex: female
Ethnicity/Population group: European Caucasoid
Geographic origin: Netherlands
Segregation observed: yes
Observation 4:
Family history: yes
Sex: female
Ethnicity/Population group: European Caucasoid
Geographic origin: Netherlands
Segregation observed: yes
Observation 5:
Family history: yes
Sex: male
Ethnicity/Population group: European Caucasoid
Geographic origin: Netherlands
Segregation observed: yes
Observation 6:
Sex: male
Ethnicity/Population group: Causasians
Geographic origin: United States
Comment on evidence:
Approximate age at death: 14 mo
Secondary finding: no
Observation 7:
Sex: female
Ethnicity/Population group: Causasians
Geographic origin: United States
Comment on evidence:
Approximate age at death: 2 years, 8 mo
Secondary finding: no
Observation 8:
Age: 30-39 years
Sex: female
Ethnicity/Population group: Causasians
Geographic origin: United States
Observation 9:
Method: in silico
Result:
(PDB: 3NW0) Leu264Phe is predicted to disrupt a fold in the NSMCE3 WH/B-e domain because of steric clashes with side-chains on the adjacent helix.
Observation 10:
Result:
The Leu264Phe mutation of the 4 affected individuals (heterozygous in 2 siblings, homozygous in 2 siblings) copurified with NSMCE1 when co expressed in E. coli but by gel filtration the complex was destabilised, consistent with disruption of the C-terminal WH/B-e domain..
Observation 11:
Method: yeast two-hybrid
Result:
The Leu264Phe mutation of the 4 affected individuals (heterozygous in 2 siblings, homozygous in 2 siblings) abolished binding of NSMCE3 to NSMCE4.
Observation 12:
Method: yeast two-hybrid
Result:
The Leu264Phe mutation of the 4 affected individuals (heterozygous in 2 siblings, homozygous in 2 siblings) mildly affected binding of NSMCE3 to NSMCE1.
Observation 13:
Result:
Co-immunoprecipitation showed that the interaction between NSMCE1 and the variant NSMCE3 Leu264Phe was slightly reduced, and the Leu264Phe variant showed reduced incorporation into the native SMC5/6 complex.
Observation 14:
Result:
NSMCE3 levels in both patient fibroblasts were dramatically reduced (levels that were below the level of detection in our assay).
Observation 15:
Result:
Significantly reduced levels of the complex subunits SMC5 and SMC6
Observation 16:
Result:
Significantly increased levels of micronuclei. Approximately 20% of cells contained micronuclei, which is similar to levels seen in ATM fibroblasts.
Observation 17:
Result:
Defect in the slow repair fraction in G2, consistent with a defect in HR.
Observation 18:
Result:
Dramatically altered response to hydroxyurea (HU), a DNA replication inhibitor.
Observation 19:
Result:
Rescue of normal HU response by expression of normal NSMCE3.
Observation 20:
Result:
Sensitivity to ionizing radiation similar to that seen with control cells from subjects with AT.
|
|
|
Pathogenic
(Jan 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002247453.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 264 of the NSMCE3 protein (p.Leu264Phe). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 264 of the NSMCE3 protein (p.Leu264Phe). This variant is present in population databases (rs199905054, gnomAD 0.02%). This missense change has been observed in individuals with NSMCE3 deficiency (PMID: 27427983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267795). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NSMCE3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NSMCE3 function (PMID: 27427983). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lung disease, immunodeficiency, and chromosome breakage syndrome;
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005076681.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: NSMCE3 c.790C>T (p.Leu264Phe) results in a non-conservative amino acid change located in the MAGE homology domain (IPR002190) of the encoded protein sequence. Three … (more)
Variant summary: NSMCE3 c.790C>T (p.Leu264Phe) results in a non-conservative amino acid change located in the MAGE homology domain (IPR002190) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. c.790C>T has been reported in the literature in multiple individuals affected with Lung Disease, Immunodeficiency, And Chromosome Breakage Syndrome (van der Crabben_2016, Willemse_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33741030, 27427983). ClinVar contains an entry for this variant (Variation ID: 267795). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 19, 2016)
|
no assertion criteria provided
Method: literature only
|
LUNG DISEASE, IMMUNODEFICIENCY, AND CHROMOSOME BREAKAGE SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000490288.1
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
Comment on evidence:
In 2 sibs, born of distantly related parents of Dutch origin, with lung disease, immunodeficiency, and chromosome breakage syndrome (LICS; 617241), van der Crabben et … (more)
In 2 sibs, born of distantly related parents of Dutch origin, with lung disease, immunodeficiency, and chromosome breakage syndrome (LICS; 617241), van der Crabben et al. (2016) identified a homozygous c.790C-T transition (rs199905054) in the NSMCE3 gene, resulting in a leu264-to-phe (L264F) substitution at a conserved residue. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. The variant was found at low frequencies in several control databases, including ExAC (4.5 x 10(-5) among Europeans; August 2015) and showed a frequency of 0.003 in the Netherlands. Two sibs from an unrelated family with a similar disorder were subsequently found to be compound heterozygous for 2 missense mutations in the NSMCE3 gene: L264F and a c.626C-T transition, resulting in a pro209-to-leu (P209L; 608243.0002) substitution at a conserved residue in the MAGE (see 300016) domain. The mutations were confirmed by Sanger sequencing and segregated with the disorder in the family. The P209L variant was not found in the ExAC database, and in vitro studies suggested that it may lead to C-terminal truncation of NSMCE3. Molecular modeling predicted that both missense mutations would destabilize the protein, and patient cells from both families showed undetectable levels of NSMCE3 as well as decreased levels of SMC5 (609386) and SMC6 (609387). In vitro studies showed that the L264F mutation abolished binding of NSMCE3 to NSMCE4 and the P209L mutation abolished binding to both NSMCE4 and NSMCE1. Patient cells showed increased sensitivity to genotoxins and impaired DNA repair due to defective homologous recombination. Nonhomologous recombination, and thus V(D)J recombination, was normal. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742198.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926819.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
Comment:
Comment on condition
Autosomal recessive syndrome due to mutations in NSMCE3 with severe progressive irreversible lung damage [HP:0002088], multiple viral induced pneumonia[HP:0011949], increased infection susceptibility (due to distinct B and T-cell abnormalities)[HP:0002719], de novo chromosome rearrangements [HP:0003220], increased sensitivity to 1 Gy of ionizing radiation [HP:0011133],
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 264 of the NSMCE3 protein (p.Leu264Phe). This variant is present in population databases (rs199905054, gnomAD 0.02%). This missense change has been observed in individuals with NSMCE3 deficiency (PMID: 27427983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267795). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NSMCE3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NSMCE3 function (PMID: 27427983). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: NSMCE3 c.790C>T (p.Leu264Phe) results in a non-conservative amino acid change located in the MAGE homology domain (IPR002190) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. c.790C>T has been reported in the literature in multiple individuals affected with Lung Disease, Immunodeficiency, And Chromosome Breakage Syndrome (van der Crabben_2016, Willemse_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33741030, 27427983). ClinVar contains an entry for this variant (Variation ID: 267795). Based on the evidence outlined above, the variant was classified as pathogenic.
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:
Four siblings from two unrelated kindreds died during infancy with markedly similar medical problems including severe pulmonary disease following viral pneumonia with evidence of combined T- and B-cell immunodeficiency. Chromosomal testing showed signs of increased aneuploidy/breakage. Cells from the subjects had increased sensitivity to DNA damage. One sib pair harbored rare (p.Leu264Phe) and novel (p.Pro209Leu) compound heterozygous missense variants in NSMCE3, while the other sib pair was homozygous for the p.Leu264Phe variant in NSMCE3.
Comment on condition
Autosomal recessive syndrome due to mutations in NSMCE3 with severe progressive irreversible lung damage [HP:0002088], multiple viral induced pneumonia[HP:0011949], increased infection susceptibility (due to distinct B and T-cell abnormalities)[HP:0002719], de novo chromosome rearrangements [HP:0003220], increased sensitivity to 1 Gy of ionizing radiation [HP:0011133],
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 264 of the NSMCE3 protein (p.Leu264Phe). This variant is present in population databases (rs199905054, gnomAD 0.02%). This missense change has been observed in individuals with NSMCE3 deficiency (PMID: 27427983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267795). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NSMCE3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NSMCE3 function (PMID: 27427983). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: NSMCE3 c.790C>T (p.Leu264Phe) results in a non-conservative amino acid change located in the MAGE homology domain (IPR002190) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. c.790C>T has been reported in the literature in multiple individuals affected with Lung Disease, Immunodeficiency, And Chromosome Breakage Syndrome (van der Crabben_2016, Willemse_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33741030, 27427983). ClinVar contains an entry for this variant (Variation ID: 267795). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS). | Willemse BWM | Orphanet journal of rare diseases | 2021 | PMID: 33741030 |
| Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease. | van der Crabben SN | The Journal of clinical investigation | 2016 | PMID: 27427983 |
| MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. | Doyle JM | Molecular cell | 2010 | PMID: 20864041 |
Text-mined citations for rs199905054 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.