This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 355 of the CAPN3 protein (p.Arg355Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 17236769, 19364062, 23821418, 29970176). ClinVar contains an entry for this variant (Variation ID: 281254). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg355 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16650086, 28403181), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1063C>T (p.Arg355Trp)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
9 out of 11 submissions contributed to this 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.
11
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000070.3(CAPN3):c.1063C>T (p.Arg355Trp)
Variation ID: 281254 Accession: VCV000281254.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q15.1 15: 42394289 (GRCh38) [ NCBI UCSC ] 15: 42686487 (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 6, 2016 Jul 13, 2025 Nov 7, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000070.3:c.1063C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Arg355Trp missense NM_024344.2:c.1063C>T NP_077320.1:p.Arg355Trp missense NM_173087.2:c.919C>T NP_775110.1:p.Arg307Trp missense NC_000015.10:g.42394289C>T NC_000015.9:g.42686487C>T NG_008660.1:g.51187C>T LRG_849:g.51187C>T LRG_849t1:c.1063C>T LRG_849p1:p.Arg355Trp - Protein change
- R355W, R307W
- Other names
- -
- Canonical SPDI
- NC_000015.10:42394288: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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
- 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. |
|||
| CAPN3 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
1834 | 1983 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 24, 2024 | RCV000389096.13 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 7, 2024 | RCV000711013.38 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 20, 2024 | RCV003463741.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 12, 2024 | RCV005008232.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 25, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000840444.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 26, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000841330.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Likely pathogenic
(Apr 03, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002025069.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 20, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy, limb-girdle, autosomal dominant 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213771.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001200165.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 355 of the CAPN3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 355 of the CAPN3 protein (p.Arg355Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 17236769, 19364062, 23821418, 29970176). ClinVar contains an entry for this variant (Variation ID: 281254). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg355 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16650086, 28403181), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 21, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331918.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 5
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Likely pathogenic
(Nov 07, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV006079369.1
First in ClinVar: May 25, 2025 Last updated: May 25, 2025 |
Comment:
Reported previously in multiple unrelated individuals with CAPN3-related disorder who also harbored a second CAPN3 pathogenic variant; however phase was undetermined in some cases (PMID: … (more)
Reported previously in multiple unrelated individuals with CAPN3-related disorder who also harbored a second CAPN3 pathogenic variant; however phase was undetermined in some cases (PMID: 27558075, 15689361, 23821418, 35135626, 19364062); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17236769, 27558075, 18073330, 23821418, 15689361, 24803842, 31555977, 29970176, 30564623, 15884399, 31069529, 17994539, 35135626, 19364062, 26404900, 18854869) (less)
|
|
|
Likely pathogenic
(Jun 12, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Muscular dystrophy, limb-girdle, autosomal dominant 4
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV005635677.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
|
|
|
Pathogenic
(Dec 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063411.26
First in ClinVar: Jan 29, 2022 Last updated: Jul 13, 2025 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 16, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454334.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Likely pathogenic
(Aug 04, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793223.3
First in ClinVar: Dec 06, 2016 Last updated: Jun 29, 2025 |
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
|
|
| click to load more submissions click to collapse | |||||
Comment:
Comment:
Reported previously in multiple unrelated individuals with CAPN3-related disorder who also harbored a second CAPN3 pathogenic variant; however phase was undetermined in some cases (PMID: 27558075, 15689361, 23821418, 35135626, 19364062); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17236769, 27558075, 18073330, 23821418, 15689361, 24803842, 31555977, 29970176, 30564623, 15884399, 31069529, 17994539, 35135626, 19364062, 26404900, 18854869)
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 355 of the CAPN3 protein (p.Arg355Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 17236769, 19364062, 23821418, 29970176). ClinVar contains an entry for this variant (Variation ID: 281254). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg355 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16650086, 28403181), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
Reported previously in multiple unrelated individuals with CAPN3-related disorder who also harbored a second CAPN3 pathogenic variant; however phase was undetermined in some cases (PMID: 27558075, 15689361, 23821418, 35135626, 19364062); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17236769, 27558075, 18073330, 23821418, 15689361, 24803842, 31555977, 29970176, 30564623, 15884399, 31069529, 17994539, 35135626, 19364062, 26404900, 18854869)
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients. | Fichna JP | Human genomics | 2018 | PMID: 29970176 |
| Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing. | Yu M | PloS one | 2017 | PMID: 28403181 |
| ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases. | Magri F | BMC neurology | 2015 | PMID: 26404900 |
| Muscle pathology in 31 patients with calpain 3 gene mutations. | Nadaj-Pakleza AA | Neurologia i neurochirurgia polska | 2013 | PMID: 23821418 |
| How to tackle the diagnosis of limb-girdle muscular dystrophy 2A. | Fanin M | European journal of human genetics : EJHG | 2009 | PMID: 18854869 |
| Phenotypic variability in siblings with calpainopathy (LGMD2A). | Schessl J | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2008 | PMID: 19364062 |
| NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A. | Benayoun B | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2008 | PMID: 18073330 |
| Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. | Guglieri M | Human mutation | 2008 | PMID: 17994539 |
| A third of LGMD2A biopsies have normal calpain 3 proteolytic activity as determined by an in vitro assay. | Milic A | Neuromuscular disorders : NMD | 2007 | PMID: 17236769 |
| Screening of the CAPN3 gene in patients with possible LGMD2A. | Krahn M | Clinical genetics | 2006 | PMID: 16650086 |
| [Calpain-3 gene defect causing limb gird muscular dystrophy in a Hungarian family]. | Horváth R | Ideggyogyaszati szemle | 2005 | PMID: 15884399 |
| LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. | Sáenz A | Brain : a journal of neurology | 2005 | PMID: 15689361 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 | - | - | - | - |
| click to load more citations click to collapse | ||||
Text-mined citations for rs749099493 ...
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 Jul 13, 2025
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.