NM_000070.3(CAPN3):c.2051-1G>T AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Nov 25, 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:: RCV000391266.16

Allele description [Variation Report for NM_000070.3(CAPN3):c.2051-1G>T]

NM_000070.3(CAPN3):c.2051-1G>T

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.2051-1G>T

Other names:

c.2099-1G>T

HGVS:

NC_000015.10:g.42409930G>T
NG_008660.1:g.66828G>T
NM_000070.3:c.2051-1G>TMANE SELECT
NM_024344.2:c.2033-1G>T
NM_173087.2:c.1775-1G>T
NM_173088.2:c.515-1G>T
NM_173089.2:c.56-1G>T
NM_173090.2:c.56-1G>T
LRG_849t1:c.2051-1G>T
LRG_849:g.66828G>T
NC_000015.9:g.42702128G>T
NM_000070.2:c.2051-1G>T

Links:

dbSNP: rs886042108

NCBI 1000 Genomes Browser:

rs886042108

Molecular consequence:

NM_000070.3:c.2051-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_024344.2:c.2033-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173087.2:c.1775-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173088.2:c.515-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173089.2:c.56-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173090.2:c.56-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1)
Synonyms:: Limb-girdle muscular dystrophy, type 2A; Limb-girdle muscular dystrophy type 2; Muscular dystrophy, pelvofemoral; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009675; MedGen: C1869123; Orphanet: 267; OMIM: 253600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000766715	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 25, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 10330340, 15689361, 23666804, 27011640, 28492532
SCV000792377	Counsyl	no assertion criteria provided	Pathogenic (Jun 21, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000844966	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	no assertion criteria provided	Pathogenic (Sep 18, 2018)	germline	clinical testing
SCV002015205	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 23666804, 27011640
SCV003922042	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27011640, 25741868
SCV004047120	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Hindu	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Calpainopathy-a survey of mutations and polymorphisms.

Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, et al.

Am J Hum Genet. 1999 Jun;64(6):1524-40.

PubMed [citation]

PMID:: 10330340
PMCID:: PMC1377896

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000766715.6

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

Description

This sequence change affects an acceptor splice site in intron 18 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 27011640). It is commonly reported in individuals of Indian ancestry (PMID: 23666804, 27011640). ClinVar contains an entry for this variant (Variation ID: 281184). 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.

#	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 Counsyl, SCV000792377.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000844966.1

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

Description

The observed variant g.50431G>T (3'splice site) has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2. The above variant was observed as compound heterozygous along with the variant c.2338G>C (p.Asp780His). The variant c.2338G>C has not been reported in 1000 Genomes and has a minor allele frequency of 0.002% in the ExAC databases. The In silico prediction of the given variant is probably damaging by PolyPhen-2 and damaging by MutationTaster2 and SIFT.

#	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

From GeneReviews, SCV002015205.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Review by ClinVar staff of the sequence in Fig. 2 or Ankala et al 2013 showed that c.2099-1G>T is actually NM_000070.2:c.2051-1G>T.

#	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 Lifecell International Pvt. Ltd, SCV003922042.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Heterozygous, Splice site acceptor variant c.2051-1G>T in Exon 18 of the CAPN3 gene that results in the amino acid substitution was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 281184) . This disorder has previously been reported in the patient affected with muscular dystrophy (Khadilkar SV et al 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047120.1

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

Description

The splice acceptor variant NM_000070.3(CAPN3) has been reported previously as a Founder mutation in the Aggarwal community (Ankala A et al) and has been described both in homozygous as well as compund heterozygous form with c.2338G>C (p.Asp780His). The variant has been submitted to ClinVar database as Pathogenic. The c.2051-1G>T variant is novel (not in any individuals) in gnomAD and 1000 Genomes. Loss of functon is the known mechanism of the disease (Baralle et al, 2005). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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