ALG10B

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

ALG10B (historically KCR1) encodes alpha-1,2-glucosyltransferase B, a glucosyltransferase that has been shown to co-precipitate with Kv11.1. Early biochemical investigations suggested that ALG10B might modulate Kv11.1 sensitivity to proarrhythmic drugs, thus playing a role in acquired (or drug induced) long QT syndrome (PMID: 14525949). An initial publication from 2010 by Hayashi et al. reported the p.Glu33Asp variant in a 70-year-old man with acquired long QT and ventricular fibrillation (PMID: 20950623). This variant is now known to have an allele frequency of 1.34 x10-4 in the East Asian population, which is inconsistent with the variant being a driver of severe Mendelian disease. In 2023, Zhou et al. suggested that ALG10B variants were a rare novel cause of autosomal dominant long QT syndrome, reporting a multigenerational pedigree with an autosomal dominant LQT2-like phenotype. A rare c.16G>A, p.Gly6Ser ALG10B variant was observed in six affected family members, although incomplete penetrance was observed, with several unaffected genotype-positive carriers being reported (PMID: 37071726). iPSC-cardiomyocyte models suggested that the p.Gly6Ser variant decreased ALG10B protein expression, with increased Kv11.1 retention in the endoplasmic reticulum and prolonged action potential duration relative to isogenic controls, prompting the authors to speculate that the variant might affect Kv11.1 trafficking (PMID: 37071726). There are no further reported rare ALG10B variants currently implicated in familial long QT syndrome. Further, ALG10B has relatively low expression in cardiac tissue (left ventricle TPM ~0.8, GTEx). Based on recent insights from gnomAD v4.1, ALG10B is not highly constrained against missense (o/e =0.96) or nonsense variation (pLI=0, LOEUF = 1.02). These constraint metrics are inconsistent with haploinsufficiency being a cause of severe Mendelian disease as suggested by Zhou et al. Overall, there is limited evidence to support a relationship between ALG10B and autosomal dominant long QT syndrome. This limited classification is based on the current absence of clinical genetic evidence, the lack of constraint against nonsense variation as well as the low ALG10B mRNA expression in cardiac tissue. This classification was approved by the ClinGen HCVD GCEP on January 13, 2026 (in accordance with SOP Version 11).

Inheritance Pattern: Unknown

Disease ID:MONDO:0013367

Submitter: Labcorp Genetics (formerly Invitae)