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

dbSNP: rs759244819

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000234879	SCV000267591	pathogenic	ALG12-congenital disorder of glycosylation	2014-04-01	criteria provided, single submitter	clinical testing	This variant was found in trans with pathogenic variant NM_024105.3:c.117delG in an individual with congenital disorder of glycosylation type Ig.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000234879	SCV001443732	pathogenic	ALG12-congenital disorder of glycosylation	2019-11-07	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001540726	SCV001758641	pathogenic	not provided	2023-07-24	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000234879	SCV002021345	likely pathogenic	ALG12-congenital disorder of glycosylation	2020-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234879	SCV002210670	pathogenic	ALG12-congenital disorder of glycosylation	2024-01-29	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002518413	SCV003687181	pathogenic	Inborn genetic diseases	2020-07-23	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000234879	SCV004813247	pathogenic	ALG12-congenital disorder of glycosylation	2024-02-27	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000234879	SCV001259211	pathogenic	ALG12-congenital disorder of glycosylation	2020-05-21	no assertion criteria provided	literature only