DNA sequence analysis of the CAPN1 gene demonstrated a sequence change located near the canonical splice donor site in intron 14, c.1605+5G>A. This sequence change has been described in the gnomAD database with a low population frequency of 0.012% (dbSNP rs375817528). This variant was identified in two symptomatic family members with spastic paraplegia in a compound heterozygous state with other frameshift variant (Gan-Or et al., 2016). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the CAPN1 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively.
ClinVar Genomic variation as it relates to human health
NM_005186.4(CAPN1):c.1605+5G>A
Germline
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)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005186.4(CAPN1):c.1605+5G>A
Variation ID: 225768 Accession: VCV000225768.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.1 11: 65206824 (GRCh38) [ NCBI UCSC ] 11: 64974295 (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 May 11, 2016 Sep 16, 2024 Jul 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005186.4:c.1605+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001198868.2:c.1605+5G>A intron variant NM_001198869.2:c.1605+5G>A intron variant NC_000011.10:g.65206824G>A NC_000011.9:g.64974295G>A NG_052817.1:g.30610G>A - Protein change
- -
- Other names
-
IVS14DS, G-A, +5
- Canonical SPDI
- NC_000011.10:65206823:G:A
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00033
- 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. |
|||
| CAPN1 | - | - |
GRCh38 GRCh37 |
246 | 297 | |
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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jul 9, 2024 | RCV000211055.24 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2022 | RCV001547189.18 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spastic paraplegia type 76
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000837704.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Weakness due to upper motor neuron dysfunction (present) , Upper motor neuron dysfunction (present) , Unsteady gait (present) , Steppage gait (present) , Spondylolisthesis at … (more)
Weakness due to upper motor neuron dysfunction (present) , Upper motor neuron dysfunction (present) , Unsteady gait (present) , Steppage gait (present) , Spondylolisthesis at L5-S1 (present) , Spasticity (present) , Proportionate short stature (present) , Premature birth (present) , Paresthesia (present) , Nystagmus (present) , Neonatal respiratory distress (present) , Lumbar spinal canal stenosis (present) , Limb dysmetria (present) , Impaired distal vibration sensation (present) , Horizontal nystagmus (present) , Headache (present) , EMG abnormality (present) , Dysarthria (present) , Distal lower limb amyotrophy (present) , Cervical spondylosis (present) , Brisk reflexes (present) , Brain atrophy (present) , Ankle clonus (present) , Abnormal pyramidal signs (present) (less)
Age: 40-49 years
Sex: male
Ethnicity/Population group: White
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-06-01
Testing laboratory interpretation: Likely pathogenic
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spastic paraplegia type 76
Affected status: yes
Allele origin:
unknown
|
Paris Brain Institute, Inserm - ICM
Accession: SCV001446327.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spastic paraplegia type 76
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760273.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
|
|
|
Likely pathogenic
(Feb 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064337.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the CAPN1 gene demonstrated a sequence change located near the canonical splice donor site in intron 14, c.1605+5G>A. This sequence change … (more)
DNA sequence analysis of the CAPN1 gene demonstrated a sequence change located near the canonical splice donor site in intron 14, c.1605+5G>A. This sequence change has been described in the gnomAD database with a low population frequency of 0.012% (dbSNP rs375817528). This variant was identified in two symptomatic family members with spastic paraplegia in a compound heterozygous state with other frameshift variant (Gan-Or et al., 2016). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the CAPN1 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. (less)
|
|
|
Pathogenic
(Oct 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002143741.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change falls in intron 14 of the CAPN1 gene. It does not directly change the encoded amino acid sequence of the CAPN1 protein. … (more)
This sequence change falls in intron 14 of the CAPN1 gene. It does not directly change the encoded amino acid sequence of the CAPN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs375817528, gnomAD 0.02%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27153400, 32214227, 33486633; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 14 and introduces a premature termination codon (PMID: 27153400). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001766837.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); This variant is associated with the following publications: (PMID: 30572172, 27153400, 32214227, … (more)
Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); This variant is associated with the following publications: (PMID: 30572172, 27153400, 32214227, 33726816, 33486633) (less)
|
|
|
Pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive spastic paraplegia type 76
Affected status: yes
Allele origin:
germline
|
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920748.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Likely pathogenic
(Jun 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spastic paraplegia type 76
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002025052.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive spastic paraplegia type 76
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005203107.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: CAPN1 c.1605+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CAPN1 c.1605+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant leads to skipping of exon 14, confirmed by cDNA sequencing (e.g. Gan-Or_2016). The variant allele was found at a frequency of 0.00012 in 242366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN1 causing Autosomal Recessive Spastic Paraplegia Type 76, allowing no conclusion about variant significance. c.1605+5G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Autosomal Recessive Spastic Paraplegia Type 76 (e.g. Gan-Or_2016, Benkirane_2021, Ek_2023), or in one compound heterozygous individual affected with a spinocerebellar ataxia (e.g. Baviera-Muoz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 37273706, 36530930, 27153400). ClinVar contains an entry for this variant (Variation ID: 225768). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(May 09, 2016)
|
no assertion criteria provided
Method: literature only
|
SPASTIC PARAPLEGIA 76, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000267865.2
First in ClinVar: May 10, 2016 Last updated: May 11, 2016 |
Comment on evidence:
For discussion of the c.1605+5G-A transition in the CAPN1 gene, resulting in a splice site mutation and the skipping of exon 14, that was found … (more)
For discussion of the c.1605+5G-A transition in the CAPN1 gene, resulting in a splice site mutation and the skipping of exon 14, that was found in compound heterozygous state in affected members of a family with spastic paraplegia-76 (SPG76; 616907) by Gan-Or et al. (2016), see 114220.0003. (less)
|
|
|
Pathogenic
(Aug 01, 2019)
|
no assertion criteria provided
Method: research
|
Autosomal recessive spastic paraplegia type 76
Affected status: yes
Allele origin:
germline
|
Section for Clinical Neurogenetics, University of Tübingen
Accession: SCV001156081.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change falls in intron 14 of the CAPN1 gene. It does not directly change the encoded amino acid sequence of the CAPN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs375817528, gnomAD 0.02%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27153400, 32214227, 33486633; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 14 and introduces a premature termination codon (PMID: 27153400). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); This variant is associated with the following publications: (PMID: 30572172, 27153400, 32214227, 33726816, 33486633)
Comment:
Variant summary: CAPN1 c.1605+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant leads to skipping of exon 14, confirmed by cDNA sequencing (e.g. Gan-Or_2016). The variant allele was found at a frequency of 0.00012 in 242366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN1 causing Autosomal Recessive Spastic Paraplegia Type 76, allowing no conclusion about variant significance. c.1605+5G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Autosomal Recessive Spastic Paraplegia Type 76 (e.g. Gan-Or_2016, Benkirane_2021, Ek_2023), or in one compound heterozygous individual affected with a spinocerebellar ataxia (e.g. Baviera-Muoz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 37273706, 36530930, 27153400). ClinVar contains an entry for this variant (Variation ID: 225768). Based on the evidence outlined above, the variant was classified as pathogenic.
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:
DNA sequence analysis of the CAPN1 gene demonstrated a sequence change located near the canonical splice donor site in intron 14, c.1605+5G>A. This sequence change has been described in the gnomAD database with a low population frequency of 0.012% (dbSNP rs375817528). This variant was identified in two symptomatic family members with spastic paraplegia in a compound heterozygous state with other frameshift variant (Gan-Or et al., 2016). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the CAPN1 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively.
Comment:
This sequence change falls in intron 14 of the CAPN1 gene. It does not directly change the encoded amino acid sequence of the CAPN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs375817528, gnomAD 0.02%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27153400, 32214227, 33486633; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 14 and introduces a premature termination codon (PMID: 27153400). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); This variant is associated with the following publications: (PMID: 30572172, 27153400, 32214227, 33726816, 33486633)
Comment:
Variant summary: CAPN1 c.1605+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant leads to skipping of exon 14, confirmed by cDNA sequencing (e.g. Gan-Or_2016). The variant allele was found at a frequency of 0.00012 in 242366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN1 causing Autosomal Recessive Spastic Paraplegia Type 76, allowing no conclusion about variant significance. c.1605+5G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Autosomal Recessive Spastic Paraplegia Type 76 (e.g. Gan-Or_2016, Benkirane_2021, Ek_2023), or in one compound heterozygous individual affected with a spinocerebellar ataxia (e.g. Baviera-Muoz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 37273706, 36530930, 27153400). ClinVar contains an entry for this variant (Variation ID: 225768). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders. | Ek M | Frontiers in neurology | 2023 | PMID: 37273706 |
| Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain. | Baviera-Muñoz R | Neurology. Genetics | 2022 | PMID: 36530930 |
| High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. | Benkirane M | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34234304 |
| Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations. | Méreaux JL | Neurogenetics | 2021 | PMID: 33486633 |
| First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. | Hengel H | European journal of human genetics : EJHG | 2020 | PMID: 32214227 |
| Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia. | Gan-Or Z | American journal of human genetics | 2016 | PMID: 27153400 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs375817528 ...
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 Sep 29, 2024
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.