NM_000070.3(CAPN3):c.1303G>A (p.Glu435Lys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Sep 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000440492.22

Allele description [Variation Report for NM_000070.3(CAPN3):c.1303G>A (p.Glu435Lys)]

NM_000070.3(CAPN3):c.1303G>A (p.Glu435Lys)

Gene:

CAPN3:calpain 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_000070.3(CAPN3):c.1303G>A (p.Glu435Lys)

HGVS:

NC_000015.10:g.42399601G>A
NG_008660.1:g.56499G>A
NM_000070.3:c.1303G>AMANE SELECT
NM_024344.2:c.1303G>A
NM_173087.2:c.1159G>A
NP_000061.1:p.Glu435Lys
NP_077320.1:p.Glu435Lys
NP_775110.1:p.Glu387Lys
LRG_849t1:c.1303G>A
LRG_849:g.56499G>A
LRG_849p1:p.Glu435Lys
NC_000015.9:g.42691799G>A
NM_000070.2:c.1303G>A

Protein change:

E387K

Links:

dbSNP: rs149914792

NCBI 1000 Genomes Browser:

rs149914792

Molecular consequence:

NM_000070.3:c.1303G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1303G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1159G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000333467	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Aug 29, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15221789, 16141003, 20635405 Citation Link,
SCV000520879	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jun 30, 2023)	germline	clinical testing	Citation Link,
SCV001143415	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (May 3, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19226146, 20635405, 16141003, 11371436, 15221789, 26467025
SCV002018073	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004041923	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Sep 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	6	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Limb-girdle muscular dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3.

Garnham CP, Hanna RA, Chou JS, Low KE, Gourlay K, Campbell RL, Beckmann JS, Davies PL.

Biochemistry. 2009 Apr 21;48(15):3457-67. doi: 10.1021/bi900130u.

PubMed [citation]

PMID:: 19226146

Transcriptional and translational effects of intronic CAPN3 gene mutations.

Nascimbeni AC, Fanin M, Tasca E, Angelini C.

Hum Mutat. 2010 Sep;31(9):E1658-69. doi: 10.1002/humu.21320.

PubMed [citation]

PMID:: 20635405
PMCID:: PMC2966865

See all PubMed Citations (7)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000333467.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		6	not provided	not provided	not provided

From GeneDx, SCV000520879.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported in the heterozygous state without a second identifiable CAPN3 variant in an individual with late onset limb girdle muscular dystrophy who had complete calpain-3 deficiency on Western blot (Fanin et al., 2004).; 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: 19226146, 16141003, 31589614, 32528171, 18854869, 11371436, 26363099, 34149409, Aksu2020[casereport], 20635405, 15221789)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV001143415.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive. Inconclusive segregation with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002018073.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004041923.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

CAPN3: PM1, PM3, PM2:Supporting, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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