ACMG categories: PS5,PM2,PP3,PP5
ClinVar Genomic variation as it relates to human health
NM_003476.5(CSRP3):c.131T>C (p.Leu44Pro)
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.
(14)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(3); Uncertain significance(4)
Pathogenic(1); Likely pathogenic(3); Uncertain significance(4)
14
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003476.5(CSRP3):c.131T>C (p.Leu44Pro)
Variation ID: 8778 Accession: VCV000008778.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.1 11: 19188286 (GRCh38) [ NCBI UCSC ] 11: 19209833 (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 Apr 4, 2013 Jun 17, 2024 Apr 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003476.5:c.131T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003467.1:p.Leu44Pro missense NM_001369404.1:c.113-1938T>C intron variant NC_000011.10:g.19188286A>G NC_000011.9:g.19209833A>G NG_011932.2:g.27288T>C LRG_440:g.27288T>C LRG_440t1:c.131T>C P50461:p.Leu44Pro - Protein change
- L44P
- Other names
- -
- Canonical SPDI
- NC_000011.10:19188285:A:G
-
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
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
- 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. |
|---|---|---|---|---|
| Likely pathogenic (3) |
criteria provided, single submitter
|
Apr 17, 2024 | RCV000009323.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 14, 2012 | RCV000037770.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 31, 2023 | RCV000627796.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000768501.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 15, 2021 | RCV000621095.5 | |
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Feb 14, 2023 | RCV001529867.10 | |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 29, 2022 | RCV003231096.1 |
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
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, University of Leuven
Accession: SCV000886806.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
|
|
|
Likely pathogenic
(Feb 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502885.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Likely pathogenic
(Dec 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV003929475.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
ACMG categories: PS5,PM2,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Atrial fibrillation (present)
Age: 60-69 years
Sex: female
Tissue: blood
|
|
|
Likely pathogenic
(Apr 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 12
Affected status: yes
Allele origin:
unknown
|
KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV005050135.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
|
|
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Uncertain significance
(Aug 14, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061432.5
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The Leu44Pro va riant in CSRP3 has been identified in 1 individual with HCM, was absent from … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The Leu44Pro va riant in CSRP3 has been identified in 1 individual with HCM, was absent from 100 0 control chromosomes and segregated with disease in 2 definitively and 1 possib ly affected relatives as well as one obligate carrier with unknown disease statu s (Geier 2003; Geier 2008). This variant was absent from two large and broad Eu ropean and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs104894205). The affected amino acid is highly conserved in evolution, suggesting that a change would impact th e protein. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) also suggest that the Leu44Pro variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, this data supports that the Leu44Pro variant may be pathoge nic but is insufficient to establish this with certainty. (less)
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003805421.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest a damaging effect; however, it is not known whether these findings are biological or clinically relevant in vivo (Lange et al., … (more)
Published functional studies suggest a damaging effect; however, it is not known whether these findings are biological or clinically relevant in vivo (Lange et al., 2016; Ehsan et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 30012424, 22429680, 18505755, 26183555, 25179549, 19115046, 27353086, 30048712, 35241752, 16352453, 25351510, 33662488, 32105245, 34495297, 31919335, 33035702, 12642359, 31513939) (less)
|
|
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Pathogenic
(Jul 31, 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: SCV000657461.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 44 of the CSRP3 protein (p.Leu44Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 44 of the CSRP3 protein (p.Leu44Pro). This variant is present in population databases (rs104894205, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12642359, 18505755; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8778). 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 disruptive. Experimental studies have shown that this missense change affects CSRP3 function (PMID: 27353086, 30048712). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Uncertain significance
(Oct 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740226.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The c.131T>C (p.L44P) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a T to C substitution … (more)
The c.131T>C (p.L44P) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a T to C substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
|
|
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Pathogenic
(Mar 18, 2003)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 12
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029541.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 brothers with hypertrophic cardiomyopathy (CMH12; 612124), Geier et al. (2003) identified heterozygosity for a T-to-C transition in exon 3 of the CSRP3 gene, … (more)
In 3 brothers with hypertrophic cardiomyopathy (CMH12; 612124), Geier et al. (2003) identified heterozygosity for a T-to-C transition in exon 3 of the CSRP3 gene, resulting in a leu44-to-pro (L44P) substitution at a highly conserved residue in the LIM1 domain. The mutation was not found in 400 patients with dilated cardiomyopathy (see 115200) or in 500 controls. (less)
|
|
|
Likely pathogenic
(Jun 25, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Hypertrophic cardiomyopathy 12
Affected status: yes
Allele origin:
germline
|
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001192742.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
|
|
Likely pathogenic
(-)
|
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: SCV001955447.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964251.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Likely 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: SCV001744072.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Likely 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: SCV001932185.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Comment:
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The Leu44Pro va riant in CSRP3 has been identified in 1 individual with HCM, was absent from 100 0 control chromosomes and segregated with disease in 2 definitively and 1 possib ly affected relatives as well as one obligate carrier with unknown disease statu s (Geier 2003; Geier 2008). This variant was absent from two large and broad Eu ropean and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs104894205). The affected amino acid is highly conserved in evolution, suggesting that a change would impact th e protein. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) also suggest that the Leu44Pro variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, this data supports that the Leu44Pro variant may be pathoge nic but is insufficient to establish this with certainty.
Comment:
Published functional studies suggest a damaging effect; however, it is not known whether these findings are biological or clinically relevant in vivo (Lange et al., 2016; Ehsan et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 30012424, 22429680, 18505755, 26183555, 25179549, 19115046, 27353086, 30048712, 35241752, 16352453, 25351510, 33662488, 32105245, 34495297, 31919335, 33035702, 12642359, 31513939)
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 44 of the CSRP3 protein (p.Leu44Pro). This variant is present in population databases (rs104894205, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12642359, 18505755; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8778). 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 disruptive. Experimental studies have shown that this missense change affects CSRP3 function (PMID: 27353086, 30048712). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.131T>C (p.L44P) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a T to C substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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:
ACMG categories: PS5,PM2,PP3,PP5
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The Leu44Pro va riant in CSRP3 has been identified in 1 individual with HCM, was absent from 100 0 control chromosomes and segregated with disease in 2 definitively and 1 possib ly affected relatives as well as one obligate carrier with unknown disease statu s (Geier 2003; Geier 2008). This variant was absent from two large and broad Eu ropean and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs104894205). The affected amino acid is highly conserved in evolution, suggesting that a change would impact th e protein. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) also suggest that the Leu44Pro variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, this data supports that the Leu44Pro variant may be pathoge nic but is insufficient to establish this with certainty.
Comment:
Published functional studies suggest a damaging effect; however, it is not known whether these findings are biological or clinically relevant in vivo (Lange et al., 2016; Ehsan et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 30012424, 22429680, 18505755, 26183555, 25179549, 19115046, 27353086, 30048712, 35241752, 16352453, 25351510, 33662488, 32105245, 34495297, 31919335, 33035702, 12642359, 31513939)
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 44 of the CSRP3 protein (p.Leu44Pro). This variant is present in population databases (rs104894205, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12642359, 18505755; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8778). 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 disruptive. Experimental studies have shown that this missense change affects CSRP3 function (PMID: 27353086, 30048712). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.131T>C (p.L44P) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a T to C substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
| Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion. | Ehsan M | Journal of molecular and cellular cardiology | 2018 | PMID: 30048712 |
| First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy. | Janin A | Gene | 2018 | PMID: 30012424 |
| 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 |
| MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy. | Lange S | Nature communications | 2016 | PMID: 27353086 |
| Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. | Geier C | Human molecular genetics | 2008 | PMID: 18505755 |
| Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. | Geier C | Circulation | 2003 | PMID: 12642359 |
Text-mined citations for rs104894205 ...
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.