ClinVar Genomic variation as it relates to human health

Observed in the heterozygous state in multiple unrelated individuals with polycystic liver disease (PMID: 28375157); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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: 25525159, 26066342, 22306853, 34426522, 31589614, 28375157, 36574950, 36938085, 37628703, 19688606)

ACMG classification criteria: PVS1, PS4, PM2, PM3

This sequence change creates a premature translational stop signal (p.Arg364*) in the ALG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG8 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs376161880, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital disorder of glycosylation type 1h (PMID: 19688606). ClinVar contains an entry for this variant (Variation ID: 280116). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The c.1090C>T (p.R364*) alteration, located in exon 10 (coding exon 10) of the ALG8 gene, consists of a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 364. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the ALG8 c.1090C>T alteration was observed in 0.01% (18/282788) of total alleles studied, with a frequency of 0.01% (14/129120) in the European (non-Finnish) subpopulation. This alteration has been detected with another mutation in patients with clinical and biochemical features consistent with congenital disorder of glycosylation type Ih, and parental testing confirmed in trans in one patient (Vesela, 2009; Höck, 2015). This alteration has also been detected in the heterozygous state in three unrelated patients with polycystic liver disease with or without renal cysts (Besse, 2017); however, this disease does not currently meet published gene-disease clinical validity criteria for this gene (Smith, 2017). Based on the available evidence, this alteration is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ih (MIM#608104) and polycystic liver disease 3 with or without kidney cysts (MIM#617874). (I) 0108 - This gene is associated with both recessive and dominant disease, where the same variants have been reported to cause both conditions (PMID: 28375157; PMID: 26066342). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (18 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants have been reported in compound heterozygous patients with congenital disorder of glycosylation (CDG) and heterozygous patients with polycystic liver disease (PLD) (Decipher, ClinVar, PMID: 28375157, PMID: 26066342). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous patients with CDG and heterozygous patients with PLD and kidney cysts (ClinVar, PMID: 28375157, PMID: 26066342, PMID: 19688606). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The ALG8 p.R364* variant was identified as a heterozygous variant in 3 of 102 individuals (frequency: 0.015) with polycystic liver disease (Besse_2017_PMID:28375157). In the compound heterozygous state, the variant has been reported in cases with congenital disorders of glycosylation Ih in probands who carried another pathogenic ALG8 variant (Vesela_2009_PMID:19688606; Hock_2015_PMID:26066342). The variant was identified in dbSNP (ID: rs376161880) and ClinVar (classified as pathogenic by GeneDx and EGL Genetics). The variant was identified in control databases in 18 of 282788 chromosomes at a frequency of 0.00006365 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 14 of 129120 chromosomes (freq: 0.000108), South Asian in 2 of 30616 chromosomes (freq: 0.000065), African in 1 of 24954 chromosomes (freq: 0.00004) and Latino in 1 of 35436 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The c.1090C>T variant leads to a premature stop codon at position 364 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ALG8 gene are an established mechanism of disease in congenital disorders of glycosylation Ih and are the type of variant expected to cause the disorder when found in the homozygous or compound heterozygous state. Loss of function variants in the ALG8 gene may also contribute to autosomal dominant polycystic liver disease. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The ALG8 c.1090C>T variant is predicted to result in premature protein termination (p.Arg364*). This variant has been reported in the compound heterozygous state in multiple individuals with congenital disorder of glycosylation type 1h (Vesela et al. 2009. PubMed ID: 19688606; Höck et al. 2015. PubMed ID: 26066342). This variant has also been reported in the heterozygous state, without a second ALG8 variant, in individuals with polycystic liver disease (Besse et al. 2017. PubMed ID: 28375157); however, there have not yet been other studies to confirm this association. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in ALG8 are expected to be pathogenic. We interpret this variant as pathogenic for autosomal recessive congenital disorder of glycosylation type 1h.