NM_024105.4(ALG12):c.1001del (p.Asn334fs) AND ALG12-congenital disorder of glycosylation

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Feb 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000234879.14

Allele description [Variation Report for NM_024105.4(ALG12):c.1001del (p.Asn334fs)]

NM_024105.4(ALG12):c.1001del (p.Asn334fs)

Gene:

ALG12:ALG12 alpha-1,6-mannosyltransferase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_024105.4(ALG12):c.1001del (p.Asn334fs)

HGVS:

NC_000022.11:g.49904499del
NG_008927.1:g.18961del
NM_024105.4:c.1001delMANE SELECT
NP_077010.1:p.Asn334fs
NC_000022.10:g.50298146del
NC_000022.10:g.50298147del
NM_024105.3:c.1001del
NM_024105.3:c.1001delA
NM_024105.4:c.1001delAMANE SELECT

Protein change:

N334fs

Links:

OMIM: 607144.0008; dbSNP: rs759244819

NCBI 1000 Genomes Browser:

rs759244819

Molecular consequence:

NM_024105.4:c.1001del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: ALG12-congenital disorder of glycosylation (CDG1G)
Synonyms:: CDG Ig; CDG 1G; Congenital disorder of glycosylation, type Ig; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011783; MedGen: C2931001; Orphanet: 79324; OMIM: 607143

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267591	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Murali et al. (Mol Genet Metab Rep. 2014))	Pathogenic (Apr 1, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001259211	OMIM	no assertion criteria provided	Pathogenic (May 21, 2020)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25019053, 31481313
SCV001443732	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002021345	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002210670	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15639192, 25019053, 31481313, 28492532
SCV004813247	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 27, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Hispanic	germline	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Molecular and clinical description of the first US patients with congenital disorder of glycosylation Ig.

Eklund EA, Newell JW, Sun L, Seo NS, Alper G, Willert J, Freeze HH.

Mol Genet Metab. 2005 Jan;84(1):25-31. Epub 2004 Nov 11.

PubMed [citation]

PMID:: 15639192

See all PubMed Citations (5)

Details of each submission

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000267591.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Hispanic	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was found in trans with pathogenic variant NM_024105.3:c.117delG in an individual with congenital disorder of glycosylation type Ig.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	1	not provided

From OMIM, SCV001259211.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002021345.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002210670.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813247.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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