rs80338800

Positions:

• chr15-42387802-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.550del​(p.Thr184ArgfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:38 O:1
• Conservation: PhyloP100: -0.895

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-42387802-CA-C is Pathogenic according to our data. Variant chr15-42387802-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 17621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42387802-CA-C is described in Lovd as [Pathogenic]. Variant chr15-42387802-CA-C is described in Lovd as [Pathogenic]. Variant chr15-42387802-CA-C is described in Lovd as [Pathogenic]. Variant chr15-42387802-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr15-42387802-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.550del	p.Thr184ArgfsTer36	frameshift_variant	4/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.550del	p.Thr184ArgfsTer36	frameshift_variant	4/23		NP_077320.1
CAPN3	NM_173087.2	c.550del	p.Thr184ArgfsTer36	frameshift_variant	4/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.550del	p.Thr184ArgfsTer36	frameshift_variant	4/24	1	NM_000070.3	ENSP00000380349	P2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251442 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 176 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74344

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000411

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:38 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:13 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Many pathogenic variants have been observed repeatedly in different populations; the c.550delA pathogenic variant is the most common allele (accounting for up to 75% of abnormal alleles) among individuals from different European countries [Richard et al 1999]. Pathogenic variant most likely the result of a founder effect followed by genetic isolation in populations in Russia, Croatia, Turkey, Czech Republic, Bulgaria, Germany, Italy, Poland, [Dincer et al 1997, Pogoda et al 2000, Canki-Klain et al 2004, Chrobakova et al 2004, Fanin et al 2005, Milic & Canki-Klain 2005, Balci et al 2006, Hanisch et al 2007, Todorova et al 2007, Stehlikova et al 2014, Dorobek et al 2015]. This pathogenic variant may have originated in the eastern Mediterranean region [Hermanova et al 2006]. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 01, 2024	Criteria applied: PVS1,PS4_MOD,PS3_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Thr184Argfs*36) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is present in population databases (rs762960425, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 7720071, 14578192, 20635405, 21204801, 21984748). ClinVar contains an entry for this variant (Variation ID: 17621). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 10, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2007	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Diseases Diagnostic Center, Koc University Hospital	Dec 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 7720071 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Thr184ArgfsTer36 variant in CAPN3 was identified by our study in the compound heterozygous state with a likely pathogenic variant in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in 8 homozygotes with LGMD increases the likelihood that the p.Thr184ArgfsTer36 variant is pathogenic (PMID: 27142102). This variant has been identified in 0.0002381% (66/277194) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762960425) as well as 9 additional individuals by our study. Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 184 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive Limb-Girdle Muscular Dystrophy. This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 17621). In summary, the clinial significance of p.Thr184ArgfsTer36 variant is pathogenic. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CAPN3 c.550delA (p.Thr184ArgfsTer36) variant is a frameshift variant that is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well reported in the literature. Across a selection of ten studies, this variant is found in over 130 patients with CAPN3-related disorders, including in 54 individuals in a homozygous state, in 44 individuals in a compound heterozygous state, and ten individuals in a heterozygous state (Richard et al. 1999; Pogoda et al. 2000; Canki-Klain et al. 2004; Piluso et al. 2005; Fanin et al. 2005; Milic et al. 2005; Krahn et al. 2006; Todorova et al. 2007; Chrobáková et al. 2004; Inashkina et al. 2016). The p.Thr184ArgfsTer36 variant was present in a heterozygous state in nine of 1691 healthy controls and is reported at a frequency of 0.005629 in the African American population of the Exome Sequencing Project. Chrobáková et al. (2004) demonstrated an absence of the CAPN3 protein on Western blots for patients who were compound heterozygous for this variant. Based on the collective evidence and the potential impact of frameshift variants, the p.Thr184ArgfsTer36 variant is classified as pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000070.2(CAPN3):c.550delA(aka T184Rfs*36) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 17318636. Classification of NM_000070.2(CAPN3):c.550delA(aka T184Rfs*36) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	This sequence change in CAPN3 is a frameshift variant predicted to cause a premature stop codon, p.(Thr184Argfs*36), in biologically relevant exon 5/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.045% (58/129,162 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is one of the most commonly reported pathogenic variants in CAPN3 and has been detected in the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy (PMID: 7720071, 14981715, 20301490). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 22, 2021	This variant is one of the most common variants associated with autosomal recessive limb girdle muscular dystrophy (PMID: 17702496, 27142102, 26484845), therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 15, 2023	PM2, PM3, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2022	Reported to be a founder mutation in European, Russian, La Reunion Island, and Amish populations (Richard et al., 1995; Canki-Klain et al., 2004; Todorova et al., 2007); Published functional studies suggest loss of normal protein function through nonsense-mediated mRNA decay (Stehlikova et al., 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21204801, 21984748, 16001438, 16100770, 19556129, 26484845, 14981715, 16141003, 20635405, 17157502, 7720071, 14578192, 17702496, 16411092, 20517216, 27142102, 17318636, 28914264, 30028523, 30919934, 31517061, 31263448, 31788660, 31862442, 32403337, 30585608, 31127727, 34426522, 34106991, 32140910, 31589614, 33726816, 32721234, 32528171) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2018	DNA sequence analysis of the CAPN3 gene demonstrated a one base pair deletion in exon 4, c.550del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 35 amino acids downstream of the varant, p.Thr184Argfs*36. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CAPN3 protein with potentially abnormal function. This pathogenic sequence change has previously been described in multiple patients with limb girdle muscular dystrophy and is reported to be a founder mutation in European, Russian and Amish populations (PMIDs: 17318636, 14981715). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CAPN3: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 01, 2023	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

CAPN3-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 19, 2024	The CAPN3 c.550delA variant is predicted to result in a frameshift and premature protein termination (p.Thr184Argfs*36). This variant is one of the most common, well documented pathogenic variants to be causative for limb girdle muscular dystrophy (Fanin et al. 2003. PubMed ID: 14578192; Richard et al. 1999. PubMed ID: 10330340). This variant is reported in 0.045% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CAPN3 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive CAPN3-related disorders. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.550delA;p.(Thr184Argfs*36) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15221789; 15725583; 20635405) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17621; PMID: 14578192; PMID: 7720071; PMID: 21984748; PMID: 17318636; PMID: 10679950; PMID: 14981715; PMID: 16100770; PMID: 21204801; PMID: 15689361; PMID: 9266733; PMID: 15725583) - PS4. The variant is present at low allele frequencies population databases (rs80338800 – gnomAD 0.001971%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr184Argfs*36) was detected in trans with a pathogenic variant (PMID: 26404900) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Muscular dystrophy;C0427063:Shoulder girdle muscle weakness;C1858127:Limb-girdle muscle weakness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Limb-girdle muscular dystrophy, recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Shoulder girdle muscle weakness;C4021726:EMG: myopathic abnormalities Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 14, 2014

- -

Shoulder girdle muscle weakness;C1843057:Calf muscle hypertrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 29, 2016

- -

Paresthesia;C0149931:Migraine;C0240914:Positive Romberg sign;C0241005:Elevated circulating creatine kinase concentration;C0311394:Difficulty walking;C4021727:EMG: neuropathic changes;C4022625:Absent muscle fiber calpain-3;C4082951:Progressive spinal muscular atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Cardiac arrhythmia;C0026850:Muscular dystrophy;C0151786:Muscle weakness;C0409338:Elbow flexion contracture;C1859523:Lower-limb joint contracture Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 24, 2014

- -

Muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PVS1_very strong;PP5_strong;PM2_supporting -

Myopathy;C0151786:Muscle weakness;C0558845:Absent Achilles reflex Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Congenital muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338800; hg19: chr15-42680000;