ClinVar Genomic variation as it relates to human health
NM_001198800.3(ASCC1):c.157dup (p.Glu53fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001198800.3(ASCC1):c.157dup (p.Glu53fs)
Variation ID: 224639 Accession: VCV000224639.11
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 72210786-72210787 (GRCh38) [ NCBI UCSC ] 10: 73970544-73970545 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 26, 2016 Feb 14, 2024 Mar 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001198800.3:c.157dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001185729.1:p.Glu53fs frameshift NM_001198798.2:c.157dup NP_001185727.1:p.Glu53fs frameshift NM_001198799.3:c.157dup NP_001185728.1:p.Glu53fs frameshift NM_001198800.2:c.157dup NM_001369085.1:c.223dup NP_001356014.1:p.Glu75fs frameshift NM_001369086.1:c.223dup NP_001356015.1:p.Glu75fs frameshift NM_001369087.1:c.157dup NP_001356016.1:p.Glu53fs frameshift NM_001369088.1:c.157dup NP_001356017.1:p.Glu53fs frameshift NM_001369089.1:c.157dup NP_001356018.1:p.Glu53fs frameshift NM_001369090.1:c.157dup NP_001356019.1:p.Glu53fs frameshift NM_001369091.1:c.157dup NP_001356020.1:p.Glu53fs frameshift NM_001369092.1:c.157dup NP_001356021.1:p.Glu53fs frameshift NM_001369093.1:c.157dup NP_001356022.1:p.Glu53fs frameshift NM_001369094.1:c.157dup NP_001356023.1:p.Glu53fs frameshift NM_001369095.1:c.157dup NP_001356024.1:p.Glu53fs frameshift NM_001369096.1:c.157dup NP_001356025.1:p.Glu53fs frameshift NM_001369097.1:c.157dup NP_001356026.1:p.Glu53fs frameshift NM_001369098.1:c.157dup NP_001356027.1:p.Glu53fs frameshift NM_001369099.1:c.223dup NP_001356028.1:p.Glu75fs frameshift NM_001369100.1:c.157dup NP_001356029.1:p.Glu53fs frameshift NM_001369101.1:c.40dup NP_001356030.1:p.Glu14fs frameshift NM_001369102.1:c.40dup NP_001356031.1:p.Glu14fs frameshift NM_001369103.1:c.157dup NP_001356032.1:p.Glu53fs frameshift NM_001369104.1:c.157dup NP_001356033.1:p.Glu53fs frameshift NM_001369105.1:c.40dup NP_001356034.1:p.Glu14fs frameshift NM_001369106.1:c.40dup NP_001356035.1:p.Glu14fs frameshift NM_001369107.1:c.40dup NP_001356036.1:p.Glu14fs frameshift NM_001369108.1:c.157dup NP_001356037.1:p.Glu53fs frameshift NM_001369109.1:c.157dup NP_001356038.1:p.Glu53fs frameshift NM_001369110.1:c.157dup NP_001356039.1:p.Glu53fs frameshift NM_001369111.1:c.157dup NP_001356040.1:p.Glu53fs frameshift NM_001369112.1:c.157dup NP_001356041.1:p.Glu53fs frameshift NR_045564.1:n.504dup non-coding transcript variant NC_000010.11:g.72210788dup NC_000010.10:g.73970546dup NG_031890.1:g.11348dup - Protein change
- E14fs, E53fs, E75fs
- Other names
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- Canonical SPDI
- NC_000010.11:72210786:CC:CCC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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ASCC1 | - | - |
GRCh38 GRCh37 |
179 | 195 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2021 | RCV000210274.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 4, 2023 | RCV001781631.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 15, 2021 | RCV001420207.2 |
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
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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. |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Spinal muscular atrophy with congenital bone fractures 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138085.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Pathogenic
(Apr 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV001622627.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
PVS1_very strong;PM3_supporting;PP5_supporting
Clinical Features:
Skeletal dysplasia (present) , Distal arthrogryposis (present) , Recurrent fractures (present)
Sex: male
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Likely pathogenic
(Oct 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Spinal muscular atrophy with congenital bone fractures 2
Affected status: yes
Allele origin:
biparental
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001985048.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Likely pathogenic
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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see cases
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV003843217.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Clinical Features:
Fetal cystic hygroma (present)
Method: Exome sequencing
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Pathogenic
(Apr 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019463.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004294752.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This premature translational stop signal has been observed in individuals with clinical features of ASCC1-related conditions (PMID: 26924529, 28218388, 30327447). It has also been observed … (more)
This premature translational stop signal has been observed in individuals with clinical features of ASCC1-related conditions (PMID: 26924529, 28218388, 30327447). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224639). This variant is present in population databases (rs753324947, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Glu53Glyfs*19) in the ASCC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASCC1 are known to be pathogenic (PMID: 30327447). (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: literature only
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SPINAL MUSCULAR ATROPHY WITH CONGENITAL BONE FRACTURES 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000266349.3
First in ClinVar: Mar 26, 2016 Last updated: Jan 13, 2020 |
Comment on evidence:
In 2 sisters (family D), born of consanguineous Turkish parents, with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867), Knierim et al. (2016) identified … (more)
In 2 sisters (family D), born of consanguineous Turkish parents, with spinal muscular atrophy with congenital bone fractures-2 (SMABF2; 616867), Knierim et al. (2016) identified a homozygous 1-bp duplication (c.157dupG, NM_001198800.2) in exon 3 of the ASCC1 gene, resulting in a frameshift and premature termination (Glu53GlyfsTer19). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The mutation was found in 2 of 120,662 alleles in the ExAC database. Patient fibroblasts showed complete absence of the ASCC1 protein. Mutant mRNA was unable to rescue the motor defects in morpholino-knockout zebrafish embryos. In a female infant, born of unrelated Portuguese parents, with SMABF2, Oliveira et al. (2017) identified a homozygous c.157dupG mutation in the ASCC1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, occurred in heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. Homozygosity mapping did not suggest high consanguinity, and the authors noted that the same mutation had been identified by Knierim et al. (2016) in a family of Middle Eastern descent. In 2 sibs, born of consanguineous parents (family 1 of Tunisian descent), with SMABF2, Bohm et al. (2019) identified homozygosity for the c.157dupG mutation in exon 3a of the ASCC1 gene. The mutation was found by direct Sanger sequencing; DNA from the unaffected parents was not available. An affected girl from a second unrelated family (family 2 of Moroccan descent) was compound heterozygous for c.157dupG and a c.466C-T transition in exon 5, resulting in an arg156-to-ter (R156X; 614215.0003) substitution. The R156X variant, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were found at a low frequency in heterozygous state in the gnomAD database (8 alleles for c.157dupG and 4 alleles for R156X). Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to result in nonsense-mediated mRNA decay and a loss of function. Bohm et al. (2019) noted that exon 3a is expressed in muscle tissue, whereas exon 3b is not. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2). | Rosano KK | American journal of medical genetics. Part A | 2021 | PMID: 33931933 |
Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures. | Böhm J | Journal of medical genetics | 2019 | PMID: 30327447 |
The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement. | Oliveira J | Clinical genetics | 2017 | PMID: 28218388 |
Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures. | Knierim E | American journal of human genetics | 2016 | PMID: 26924529 |
Text-mined citations for rs753324947 ...
HelpRecord last updated May 12, 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.