rs80338800
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PP1PP4_StrongPM3
This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.550del p.(Thr184ArgfsTer36) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant is one of the most common disease-causing variants in CAPN3 reported in patients with Eastern European and Mediterranean ancestry (PMID:25900067). It has been detected in at least 36 individuals with LGMD (PMID:17236769, 17994539, 26404900, 30919934, 31788660, 17702496, 27142102). Of those individuals, at least 11 were compound heterozygous and 18 were homozygous (1.0 pt) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID:17236769). The variant has also been reported to segregate with LGMD in two affected family members from two families (PP1, capped with PP4_Strong; PMID:30919934). The filtering allele frequency of the variant is 0.0005368 for European (non-Finnish) exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 48/113726), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4_Strong, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220352/MONDO:0015152/187
Frequency
Consequence
NM_000070.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CAPN3 | NM_000070.3 | c.550delA | p.Thr184ArgfsTer36 | frameshift_variant | Exon 4 of 24 | ENST00000397163.8 | NP_000061.1 | |
| CAPN3 | NM_024344.2 | c.550delA | p.Thr184ArgfsTer36 | frameshift_variant | Exon 4 of 23 | NP_077320.1 | ||
| CAPN3 | NM_173087.2 | c.550delA | p.Thr184ArgfsTer36 | frameshift_variant | Exon 4 of 21 | NP_775110.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CAPN3 | ENST00000397163.8 | c.550delA | p.Thr184ArgfsTer36 | frameshift_variant | Exon 4 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
| ENSG00000258461 | ENST00000495723.1 | n.*346delA | non_coding_transcript_exon_variant | Exon 8 of 26 | 2 | ENSP00000492063.1 | ||||
| ENSG00000258461 | ENST00000495723.1 | n.*346delA | 3_prime_UTR_variant | Exon 8 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes 0.000197 AC: 30AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251442Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135892
GnomAD4 exome AF: 0.000233 AC: 341AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 176AN XY: 727238
GnomAD4 genome 0.000197 AC: 30AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74344
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:15Other:1
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Predicted Consequence/Location: Frameshift: 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 (ClinVar ID: VCV000017621 /PMID: 7720071 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
PM2_Supporting+PVS1+PM3_VeryStrong -
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. -
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). -
Criteria applied: PVS1,PS4_MOD,PS3_SUP -
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. -
- -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive limb-girdle muscular dystrophy 1 (MIM#253600). Dominant negative mechanism is a suggested mechanism for dominant limb-girdle muscular dystrophy 4 (MIM#618129) associated with milder phenotypes and later age of onset (ClinVar, PMID: 27259757). (I) 0108 - This gene is associated with both recessive and dominant disease. It is predominantly reported as a recessive condition, with the dominant condition reported with only a few missense variants and one in-frame deletion (PMID: 27259757, 28881388, 31066050). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (65 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and have been observed in multiple homozygous and compound heterozygous individuals with limb girdle muscular dystrophy (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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. -
- -
- -
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]. -
- -
- -
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. -
- -
not provided Pathogenic:10
- -
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). -
- -
PM2, PM3, PS4_moderate, PVS1 -
CAPN3: PM3:Very Strong, PVS1, PM2 -
- -
- -
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. -
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) -
- -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:2
This variant was classified as: Pathogenic. -
- -
CAPN3-related disorder Pathogenic:2
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. -
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. -
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
The NM_000070.3: c.550del p.(Thr184ArgfsTer36) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant is one of the most common disease-causing variants in CAPN3 reported in patients with Eastern European and Mediterranean ancestry (PMID: 25900067). It has been detected in at least 36 individuals with LGMD (PMID: 17236769, 17994539, 26404900, 30919934, 31788660, 17702496, 27142102). Of those individuals, at least 11 were compound heterozygous and 18 were homozygous (1.0 pt) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17236769). The variant has also been reported to segregate with LGMD in two affected family members from two families (PP1, capped with PP4_Strong; PMID: 30919934). The filtering allele frequency of the variant is 0.0005368 for European (non-Finnish) exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 48/113726), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4_Strong, PP1. -
Muscular dystrophy;C0427063:Shoulder girdle muscle weakness;C1858127:Limb-girdle muscle weakness Pathogenic:1
- -
Limb-girdle muscular dystrophy, recessive Pathogenic:1
- -
Shoulder girdle muscle weakness;C4021726:EMG: myopathic abnormalities Pathogenic:1
- -
Shoulder girdle muscle weakness;C1843057:Calf muscle hypertrophy Pathogenic:1
- -
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
- -
Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
- -
Cardiac arrhythmia;C0026850:Muscular dystrophy;C0151786:Muscle weakness;C0409338:Elbow flexion contracture;C1859523:Lower-limb joint contracture Pathogenic:1
- -
Muscular dystrophy Pathogenic:1
- -
See cases Pathogenic:1
PVS1_very strong;PP5_strong;PM2_supporting -
Myopathy;C0151786:Muscle weakness;C0558845:Absent Achilles reflex Pathogenic:1
- -
Congenital muscular dystrophy Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at