The p.T179A variant (also known as c.535A>G), located in coding exon 5 of the CSRP3 gene, results from an A to G substitution at nucleotide position 535. The threonine at codon 179 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in a dilated cardiomyopathy cohort (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ClinVar Genomic variation as it relates to human health
NM_003476.5(CSRP3):c.535A>G (p.Thr179Ala)
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.
(9)
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.
Uncertain significance
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003476.5(CSRP3):c.535A>G (p.Thr179Ala)
Variation ID: 44701 Accession: VCV000044701.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.1 11: 19182720 (GRCh38) [ NCBI UCSC ] 11: 19204267 (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 Jan 31, 2015 Jul 23, 2024 Oct 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003476.5:c.535A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003467.1:p.Thr179Ala missense NM_001369404.1:c.366A>G NP_001356333.1:p.Pro122= synonymous NC_000011.10:g.19182720T>C NC_000011.9:g.19204267T>C NG_011932.2:g.32854A>G LRG_440:g.32854A>G LRG_440t1:c.535A>G - Protein change
- T179A
- Other names
- -
- Canonical SPDI
- NC_000011.10:19182719:T:C
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
- 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. |
|||
| CSRP3 | - | - |
GRCh38 GRCh37 |
420 | 458 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
Mar 22, 2009 | RCV000037787.6 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2023 | RCV000700094.9 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
May 26, 2020 | RCV000769295.4 | |
| Uncertain significance (3) |
criteria provided, single submitter
|
Oct 18, 2023 | RCV001699187.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 16, 2023 | RCV003298069.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900673.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
|
|
|
Uncertain significance
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003993233.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The p.T179A variant (also known as c.535A>G), located in coding exon 5 of the CSRP3 gene, results from an A to G substitution at nucleotide … (more)
The p.T179A variant (also known as c.535A>G), located in coding exon 5 of the CSRP3 gene, results from an A to G substitution at nucleotide position 535. The threonine at codon 179 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in a dilated cardiomyopathy cohort (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Mar 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 12
Dilated cardiomyopathy 1M
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000828835.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 44701). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant is present in population databases (rs397516859, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 179 of the CSRP3 protein (p.Thr179Ala). (less)
|
|
|
Uncertain significance
(Oct 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000492237.4
First in ClinVar: Jan 31, 2015 Last updated: Jul 23, 2024 |
Comment:
Reported in individuals with DCM (PMID: 20474083, 24503780, 27532257); Observed in an individual referred for genetic testing at GeneDx who also had a likely pathogenic … (more)
Reported in individuals with DCM (PMID: 20474083, 24503780, 27532257); Observed in an individual referred for genetic testing at GeneDx who also had a likely pathogenic variant in a different cardiomyopathy-related gene that segregated with disease in the family; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780, 30847666, 20474083) (less)
|
|
|
Uncertain significance
(May 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767686.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to alanine (Exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (4 heterozygotes). (P) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD: p.(Thr179Met) 0.003% (8 heterozygotes), p.(Thr179Arg) 0.0004% (1 heterozygote). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Thr179Met) - one likely pathogenic and three VUS entries in ClinVar. (N) 0808 - Previous reports of pathogenicity are uncertain. Four VUS entries in ClinVar. Reported as a VUS in a DCM patient and a cardiomyopathy patient (PMID: 24503780, PMID: 30847666). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) - Benign (less)
|
|
|
Uncertain significance
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1M
Hypertrophic cardiomyopathy 12
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002787290.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Mar 22, 2009)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061449.4
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925836.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956605.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
Comment:
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 44701). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant is present in population databases (rs397516859, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 179 of the CSRP3 protein (p.Thr179Ala).
Comment:
Reported in individuals with DCM (PMID: 20474083, 24503780, 27532257); Observed in an individual referred for genetic testing at GeneDx who also had a likely pathogenic variant in a different cardiomyopathy-related gene that segregated with disease in the family; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780, 30847666, 20474083)
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to alanine (Exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (4 heterozygotes). (P) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD: p.(Thr179Met) 0.003% (8 heterozygotes), p.(Thr179Arg) 0.0004% (1 heterozygote). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Thr179Met) - one likely pathogenic and three VUS entries in ClinVar. (N) 0808 - Previous reports of pathogenicity are uncertain. Four VUS entries in ClinVar. Reported as a VUS in a DCM patient and a cardiomyopathy patient (PMID: 24503780, PMID: 30847666). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) - Benign
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:
The p.T179A variant (also known as c.535A>G), located in coding exon 5 of the CSRP3 gene, results from an A to G substitution at nucleotide position 535. The threonine at codon 179 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in a dilated cardiomyopathy cohort (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 44701). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant is present in population databases (rs397516859, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 179 of the CSRP3 protein (p.Thr179Ala).
Comment:
Reported in individuals with DCM (PMID: 20474083, 24503780, 27532257); Observed in an individual referred for genetic testing at GeneDx who also had a likely pathogenic variant in a different cardiomyopathy-related gene that segregated with disease in the family; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780, 30847666, 20474083)
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to alanine (Exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (4 heterozygotes). (P) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD: p.(Thr179Met) 0.003% (8 heterozygotes), p.(Thr179Arg) 0.0004% (1 heterozygote). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Thr179Met) - one likely pathogenic and three VUS entries in ClinVar. (N) 0808 - Previous reports of pathogenicity are uncertain. Four VUS entries in ClinVar. Reported as a VUS in a DCM patient and a cardiomyopathy patient (PMID: 24503780, PMID: 30847666). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) - Benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. | Mazzarotto F | Circulation | 2020 | PMID: 31983221 |
| Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
| Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
| The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Text-mined citations for rs397516859 ...
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.