ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic
- Review status:
- no assertion criteria provided
- Submissions:
- 1
- First in ClinVar:
- Aug 20, 2021
- Most recent Submission:
- Aug 20, 2021
- Last evaluated:
- Aug 16, 2021
- Accession:
- VCV001202617.1
- Variation ID:
- 1202617
- Description:
- single nucleotide variant
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NM_173491.4(LSM11):c.631G>A (p.Gly211Ser)
- Allele ID
- 1192619
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 5q33.3
- Genomic location
- 5: 157754046 (GRCh38) GRCh38 UCSC
- 5: 157181054 (GRCh37) GRCh37 UCSC
- HGVS
-
Nucleotide Protein Molecular
consequenceNM_173491.4:c.631G>A MANE Select NP_775762.1:p.Gly211Ser missense NC_000005.10:g.157754046G>A NC_000005.9:g.157181054G>A - Protein change
- G211S
- Other names
- -
- Canonical SPDI
- NC_000005.10:157754045:G:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- OMIM: 617910.0001
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 1 | no assertion criteria provided | Aug 16, 2021 | RCV001568350.1 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Aug 16, 2021)
|
no assertion criteria provided
Method: literature only
|
AICARDI-GOUTIERES SYNDROME 8 (1 family)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001792206.1
First in ClinVar: Aug 20, 2021 Last updated: Aug 20, 2021 |
Comment on evidence:
In 2 Pakistani brothers (family AGS114) who died at age 2 years with Aicardi-Goutieres syndrome (AGS8; 619486), Uggenti et al. (2020) identified homozygosity for a … (more)
In 2 Pakistani brothers (family AGS114) who died at age 2 years with Aicardi-Goutieres syndrome (AGS8; 619486), Uggenti et al. (2020) identified homozygosity for a c.631G-A transition (c.631G-A, NM_173491.3) in the LSM11 gene, resulting in a gly211-to-ser (G211S) substitution at a highly conserved residue. Their unaffected first-cousin parents were heterozygous for the mutation, which was not found in public variant databases. RT-qPCR in patient fibroblasts revealed enrichment for aberrantly polyadenylated forms of replication-dependent histone (RDH) mRNAs derived from different histone clusters. Similar changes were observed after siRNA knockdown of LSM11 in HEK293T, HCT116, and U2OS cells. Histone expression analysis showed reduced levels of HIST1H1E (142220), encoding the linker histone H1.4, in patient-derived fibroblasts compared to controls. Genomewide transcript expression analysis revealed a global increase in polyadenylated RDH mRNA transcripts in patient cells, with a concomitant reduction in mature nonpolyadenylated RDH gene transcripts. The authors concluded that G211S is a loss-of-function variant that disturbs RDH pre-mRNA processing. An ex vivo assay of interferon signaling status in patient blood showed upregulation of interferon-stimulated genes (ISGs), and there was increased expression of ISGs in patient fibroblasts. Histone subtype-specific antibodies revealed a marked reduction in the ratio of linker H1.4 to H1.2 in patient cells compared to controls, whereas the levels of core histones showed no difference. Wide-field microscopy and immunofluorescence demonstrated an altered nuclear distribution of CGAS (613973) in patient fibroblasts compared to controls, and patient cells also exhibited an increased frequency of misshapen nuclei, including nuclear membrane herniations with intense foci of CGAS. (less)
|
Functional evidence
Help| 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. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. | Uggenti C | Nature genetics | 2020 | PMID: 33230297 |
Record last updated Jun 11, 2022