Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Research Center, |
RCV000002210 | SCV000930496 | pathogenic | ALG3-congenital disorder of glycosylation | 2023-12-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000002210 | SCV002239406 | pathogenic | ALG3-congenital disorder of glycosylation | 2023-07-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 15108280, 31067009). ClinVar contains an entry for this variant (Variation ID: 2128). This variant has been observed in individual(s) with ALG3-congenital disorder of glycosylation (PMID: 15108280, 27172925, 31067009). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 55 of the ALG3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALG3 protein. |
| Broad Center for Mendelian Genomics, |
RCV000002210 | SCV003922108 | likely pathogenic | ALG3-congenital disorder of glycosylation | 2023-05-02 | criteria provided, single submitter | curation | The homozygous c.154+6C>T variant in ALG3 was identified by our study in two siblings with facial dysmorphism, muscle weakness, absent speech, and delayed gross motor development (PMID: 32389449). The c.154+6C>T variant in ALG3 has been previously reported in three individuals with congenital disorder of glycosylation type 1d (PMID: 15108280, PMID: 27172925, PMID: 28122681), but has been identified in 0.003% (2/65800) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs387906273). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 2128) with conflicting interpretations of pathogenicity. Of the 3 affected individuals previously reported, two were homozygotes (PMID: 28122681, PMID: 15108280) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 27172925, ClinVar Variation ID: 1053045), which increases the likelihood that the c.154+6C>T variant is pathogenic. The phenotype of two individuals homozygous for this variant is highly specific for congenital disorder of glycosylation type 1d based on their abnormal lipid-linked oligosaccharide profiles including the presence of truncated Man5-GlcNAc2, consistent with disease (PMID: 28122681, PMID: 15108280). RT-PCR analysis of RNA from affected tissue showed altered splicing of exon 1, leading to a 35bp deletion (c.160_196del), frameshift, and premature truncation (PMID: 15108280). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive congenital disorder of glycosylation type 1d. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PM3, PP4 (Richards 2015). |
| OMIM | RCV000002210 | SCV000022368 | pathogenic | ALG3-congenital disorder of glycosylation | 2005-08-01 | no assertion criteria provided | literature only |