ClinVar Genomic variation as it relates to human health
NM_022173.4(TIA1):c.1150G>A (p.Glu384Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_022173.4(TIA1):c.1150G>A (p.Glu384Lys)
Variation ID: 41480 Accession: VCV000041480.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.3 2: 70212730 (GRCh38) [ NCBI UCSC ] 2: 70439862 (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 Dec 19, 2017 Mar 10, 2024 Dec 15, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_022173.4:c.1150G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071505.2:p.Glu384Lys missense NM_001351508.2:c.1147G>A NP_001338437.1:p.Glu383Lys missense NM_001351509.2:c.1123G>A NP_001338438.1:p.Glu375Lys missense NM_001351510.2:c.1114G>A NP_001338439.1:p.Glu372Lys missense NM_001351511.1:c.1039G>A NP_001338440.1:p.Glu347Lys missense NM_001351512.1:c.1012G>A NP_001338441.1:p.Glu338Lys missense NM_001351513.1:c.1006G>A NP_001338442.1:p.Glu336Lys missense NM_001351514.2:c.922G>A NP_001338443.1:p.Glu308Lys missense NM_001351515.2:c.847G>A NP_001338444.1:p.Glu283Lys missense NM_001351517.2:c.727G>A NP_001338446.1:p.Glu243Lys missense NM_001351524.2:c.730G>A NP_001338453.1:p.Glu244Lys missense NM_001351525.2:c.730G>A NP_001338454.1:p.Glu244Lys missense NM_022037.4:c.1117G>A NP_071320.2:p.Glu373Lys missense NR_147216.1:n.1507G>A non-coding transcript variant NR_147217.1:n.1388G>A non-coding transcript variant NR_147218.1:n.1385G>A non-coding transcript variant NR_147219.2:n.1457G>A non-coding transcript variant NR_147220.2:n.1443G>A non-coding transcript variant NR_147221.2:n.1514G>A non-coding transcript variant NR_147222.2:n.1509G>A non-coding transcript variant NR_147223.2:n.1567G>A non-coding transcript variant NR_147224.2:n.1445G>A non-coding transcript variant NR_147225.2:n.1600G>A non-coding transcript variant NR_147226.2:n.1448G>A non-coding transcript variant NR_147227.2:n.1518G>A non-coding transcript variant NR_147228.2:n.1481G>A non-coding transcript variant NR_147229.2:n.1424G>A non-coding transcript variant NR_147230.2:n.1666G>A non-coding transcript variant NR_147231.2:n.1478G>A non-coding transcript variant NR_147232.2:n.1351G>A non-coding transcript variant NC_000002.12:g.70212730C>T NC_000002.11:g.70439862C>T NG_029967.1:g.40918G>A P31483:p.Glu384Lys - Protein change
- E384K, E243K, E308K, E336K, E244K, E372K, E373K, E383K, E283K, E338K, E347K, E375K
- Other names
- -
- Canonical SPDI
- NC_000002.12:70212729:C:T
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
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. |
|||
TIA1 | - | - |
GRCh38 GRCh37 |
277 | 290 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2019 | RCV000267511.9 | |
Pathogenic (2) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV000576901.16 |
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
(Jul 01, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450108.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 55
|
|
Pathogenic
(Aug 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000330041.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (increase in stress granule abundance) (Hackman et al., 2013); This variant is associated with the following publications: (PMID: … (more)
Published functional studies demonstrate a damaging effect (increase in stress granule abundance) (Hackman et al., 2013); This variant is associated with the following publications: (PMID: 23348830, 23401021, 10482271, 27282841, 28221306, 28817800, 30348846, 31321302, 33144682) (less)
|
|
Pathogenic
(Mar 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018969.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Welander distal myopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000964805.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 384 of the TIA1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 384 of the TIA1 protein (p.Glu384Lys). This variant is present in population databases (rs747068278, gnomAD 0.007%). This missense change has been observed in individuals with Welander distal myopathy (WDM) (PMID: 10482271, 23348830, 23401021, 27282841). It is commonly reported in individuals of Finnish ancestry (PMID: 10482271, 23348830, 23401021, 27282841). ClinVar contains an entry for this variant (Variation ID: 41480). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TIA1 function (PMID: 23401021, 28817800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 01, 2013)
|
no assertion criteria provided
Method: literature only
|
WELANDER DISTAL MYOPATHY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000678313.4
First in ClinVar: Jan 15, 2018 Last updated: Mar 10, 2024 |
Comment on evidence:
By targeted high-throughput sequencing and Sanger sequencing of the candidate Welander distal myopathy (WDM; 604454) region on chromosome 2p13, Hackman et al. (2013) identified a … (more)
By targeted high-throughput sequencing and Sanger sequencing of the candidate Welander distal myopathy (WDM; 604454) region on chromosome 2p13, Hackman et al. (2013) identified a heterozygous 1362G-A transition in exon 13 of the TIA1 gene, resulting in a glu384-to-lys (E384K; 603518.0001) substitution that segregated with the disorder in all 57 Swedish and Finnish patients studied. The same mutation was also found in 3 patients from Great Britain who had a partially shared haplotype with the Nordic patients, indicating common ancestry. The mutation was not found in 202 Finnish control samples. The E384K mutation occurred at a highly conserved residue in the RNA-binding domain of the protein at the C terminus, also known as the prion-related domain that is required for TIA1 aggregation in stress granules. Immunofluorescence microscopy of patient muscle showed diffuse TIA1-labeled cytoplasmic aggregates or granules in some atrophic fibers and fibers containing rimmed vacuoles. However, most fibers appeared normal and had normal TIA1 nuclear localization. Analysis of TIA1 splice isoforms and protein stability showed no consistent differences between WDM muscle and control muscle. Expression of the mutant protein in HeLa cells resulted in a mild increased (10-20%) of stress granule numbers compared to controls. The increased number was apparently due to a change in stress-granule dynamics resulting from a gain of function. Klar et al. (2013) also restricted the WDM-associated haplotype and performed exome sequencing of 43 patients from 35 families with the disorder. They identified a heterozygous E384K mutation resulting from a 1150G-A transition in the TIA1 gene and occurring in a Q-rich domain. The mutation was not found in 800 control chromosomes. Patient muscle biopsies showed increased splicing of exon 7 of the SMN2 gene (601627), reflecting impaired TIA1 function. Klar et al. (2013) hypothesized that reduced activity of TIA1 may result in decreased response to cellular stress, such as oxidative stress, that may cause age-related cellular atrophy in patients carrying the mutation. The age of the mutation was estimated to be 1,050 years earlier, coinciding with the epoch of early seafaring across the Baltic Sea. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. | Mackenzie IR | Neuron | 2017 | PMID: 28817800 |
Distal myopathy with coexisting heterozygous TIA1 and MYH7 Variants. | Brand P | Neuromuscular disorders : NMD | 2016 | PMID: 27282841 |
Genetic linkage of Welander distal myopathy to chromosome 2p13. | Ahlberg G | Annals of neurology | 1999 | PMID: 10482271 |
Text-mined citations for rs747068278 ...
HelpRecord last updated Jun 23, 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.