ClinVar Genomic variation as it relates to human health
NM_024105.4(ALG12):c.1001del (p.Asn334fs)
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_024105.4(ALG12):c.1001del (p.Asn334fs)
Variation ID: 242854 Accession: VCV000242854.19
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 49904498 (GRCh38) [ NCBI UCSC ] 22: 50298146 (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 Jul 9, 2016 May 1, 2024 Feb 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024105.4:c.1001del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077010.1:p.Asn334fs frameshift NM_024105.4:c.1001delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024105.3:c.1001del NC_000022.11:g.49904499del NC_000022.10:g.50298147del NG_008927.1:g.18961del - Protein change
- N334fs
- Other names
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- Canonical SPDI
- NC_000022.11:49904497:TT:T
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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ALG12 | - | - |
GRCh38 GRCh37 |
526 | 764 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Feb 27, 2024 | RCV000234879.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2023 | RCV001540726.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 23, 2020 | RCV002518413.2 |
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
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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
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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
(Apr 01, 2014)
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criteria provided, single submitter
Method: clinical testing
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ALG12-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000267591.1
First in ClinVar: Jul 09, 2016 Last updated: Jul 09, 2016 |
Comment:
This variant was found in trans with pathogenic variant NM_024105.3:c.117delG in an individual with congenital disorder of glycosylation type Ig.
Number of individuals with the variant: 1
Clinical Features:
Rhizomelia (present) , Talipes equinovarus (present) , Joint dislocation (present)
Sex: female
Ethnicity/Population group: Hispanic
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Pathogenic
(Nov 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ig
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001443732.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This frameshifting variant in exon 8 of 10 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. … (more)
This frameshifting variant in exon 8 of 10 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with Congenital disorder of glycosylation type Ig (PMID: 25019053). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0052% (13/251142) and thus is presumed to be rare. Based on the available evidence, the c.1001del (p.Asn334ThrfsTer15) variant is classified as Pathogenic. (less)
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Pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001758641.5
First in ClinVar: Jul 24, 2021 Last updated: Jul 29, 2023 |
Comment:
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 … (more)
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: 31589614, 31481313, 33144682, 25019053, 33413482) (less)
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Likely pathogenic
(Feb 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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ALG12-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021345.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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ALG12-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002210670.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn334Thrfs*15) in the ALG12 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asn334Thrfs*15) in the ALG12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG12 are known to be pathogenic (PMID: 15639192, 31481313). This variant is present in population databases (rs759244819, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of congenital disorders of glycosylation (PMID: 25019053, 31481313). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242854). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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ALG12-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813247.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: ALG12 c.1001delA (p.Asn334ThrfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ALG12 c.1001delA (p.Asn334ThrfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 251142 control chromosomes. c.1001delA has been reported in the literature in individuals affected with ALG12-Congenital Disorder Of Glycosylation (e.g. Murali_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25019053). ClinVar contains an entry for this variant (Variation ID: 242854). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003687181.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1001delA (p.N334Tfs*15) alteration, located in exon 8 (coding exon 7) of the ALG12 gene, … (more)
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1001delA (p.N334Tfs*15) alteration, located in exon 8 (coding exon 7) of the ALG12 gene, results from a deletion of one nucleotide at position 1001, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the ALG12 c.1001delA alteration was observed in <0.01% (13/251142) of total alleles studied, with a frequency of 0.03% (9/34584) in the Latino subpopulation. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported with another frameshift alteration, c.117delG (p.Q40Rfs*34), in ALG12 in an infant with rhizomelic short stature, talipes equinovarus, platyspondyly, and joint dislocations (Murali, 2014). Tahata, et al. (2019) reported this alteration in trans with c.671C>T (p.T224M) in two affected brothers who only had cognitive impairment and coagulation defects. They also had a younger brother who died from a severe multisystem disease at age 18 months and was suspected of having congenital disorder of glycosylation. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(May 21, 2020)
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no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ig
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001259211.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment on evidence:
By whole-exome sequencing in a Hispanic female infant (patient R82-101) with congenital disorder of glycosylation type Ig (CDG1G; 607143), Murali et al. (2014) identified compound … (more)
By whole-exome sequencing in a Hispanic female infant (patient R82-101) with congenital disorder of glycosylation type Ig (CDG1G; 607143), Murali et al. (2014) identified compound heterozygosity for 2 deletions in the ALG12 gene: c.1001delA (c.1001delA, NM_024105.3), resulting in a frameshift and a premature termination codon (Asn334ThrfsTer15), and c.117delG (607144.0009), resulting in a frameshift and a premature termination codon (Gln40ArgfsTer34). The patient had severe skeletal anomalies including interphalangeal dislocations, scoliosis, talipes equinovarus, rhizomelic limb shortening, midface hypoplasia, short metacarpals, and a somewhat horizontal acetabular roof suggestive of pseudodiastrophic dysplasia. She also had ulnar deviation of the wrists. She required mechanical ventilation at birth and died in the neonatal period. For discussion of the c.1001delA mutation in the ALG12 gene that was found in compound heterozygous state in 2 adult male sibs with a mild form of congenital disorder of glycosylation type Ig (CDG1G; 607143) by Tahata et al. (2019), see 607144.0007. (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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Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature. | Tahata S | Molecular genetics and metabolism | 2019 | PMID: 31481313 |
Diagnosis of ALG12-CDG by exome sequencing in a case of severe skeletal dysplasia. | Murali C | Molecular genetics and metabolism reports | 2014 | PMID: 25019053 |
Molecular and clinical description of the first US patients with congenital disorder of glycosylation Ig. | Eklund EA | Molecular genetics and metabolism | 2005 | PMID: 15639192 |
Text-mined citations for rs759244819 ...
HelpRecord last updated May 01, 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.