ClinVar Genomic variation as it relates to human health

Ataxia-Pancytopenia Syndrome In 7 affected members of a 3-generation family of Swedish origin (family 1) with variable manifestations of ataxia-pancytopenia syndrome (ATXPC; 159550), Tesi et al. (2017) identified a heterozygous c.2956C-T transition (c.2956C-T, ENST00000318238) in the SAMD9L gene, resulting in an arg986-to-cys (R986C) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ExAC database. In vitro functional expression studies in cells transfected with the mutation showed that it augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. The proband was a 6-year-old boy with pancytopenia and myelodysplastic syndrome (MDS) who also had monosomy 7. He underwent bone marrow transplantation and later developed neurologic symptoms. His grandfather developed MDS at age 56 years: he did not have monosomy 7. He had mildly impaired balance. None of the other affected family members had MDS, but several had transient thrombocytopenia or pancytopenia, often associated with uniparental disomy of chromosome 7q or a revertant SAMD9L variant. One unaffected 38-year-old woman who carried the R986C mutation also carried a T233N variant in the SAMD9L gene, which represented a disease-modifying loss-of-function variant that presumably mitigated the effects of the R986C mutation. Monosomy 7 Myelodysplasia and Leukemia Syndrome 1 In 2 sisters (family 3) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a germline heterozygous R986C mutation in the SAMD9L gene. In vitro cellular studies demonstrated a growth-suppressive effect of the mutation. The proband presented with MDS and monosomy 7. She underwent successful bone marrow transplantation and was well at age 27 years. Genetic studies of her sister, who had no overt hematologic abnormalities, detected a focal somatic deletion of 7q11-q36, which contains the SAMD9L gene, in 7 of 27 metaphase cells. She died of an unrelated cause at age 27 years. Their unaffected mother also carried the R986C mutation. All 3 individuals carried additional, but different, putative revertant variants in the SAMD9L gene (F1092L, R223X, R843W, Y568C, and E276X) that were demonstrated or predicted to abrogate the growth-suppressive properties of the R986C substitution. The authors postulated that the relatively mild clinical course in this family may have been due to the additional revertant SAMD9L variants or to a low level of monosomy 7. (less)

Ataxia-Pancytopenia Syndrome In 7 affected members of a 3-generation family of Swedish origin (family 1) with variable manifestations of ataxia-pancytopenia syndrome (ATXPC; 159550), Tesi et al. (2017) identified a heterozygous c.2956C-T transition (c.2956C-T, ENST00000318238) in the SAMD9L gene, resulting in an arg986-to-cys (R986C) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ExAC database. In vitro functional expression studies in cells transfected with the mutation showed that it augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. The proband was a 6-year-old boy with pancytopenia and myelodysplastic syndrome (MDS) who also had monosomy 7. He underwent bone marrow transplantation and later developed neurologic symptoms. His grandfather developed MDS at age 56 years: he did not have monosomy 7. He had mildly impaired balance. None of the other affected family members had MDS, but several had transient thrombocytopenia or pancytopenia, often associated with uniparental disomy of chromosome 7q or a revertant SAMD9L variant. One unaffected 38-year-old woman who carried the R986C mutation also carried a T233N variant in the SAMD9L gene, which represented a disease-modifying loss-of-function variant that presumably mitigated the effects of the R986C mutation. Monosomy 7 Myelodysplasia and Leukemia Syndrome 1 In 2 sisters (family 3) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a germline heterozygous R986C mutation in the SAMD9L gene. In vitro cellular studies demonstrated a growth-suppressive effect of the mutation. The proband presented with MDS and monosomy 7. She underwent successful bone marrow transplantation and was well at age 27 years. Genetic studies of her sister, who had no overt hematologic abnormalities, detected a focal somatic deletion of 7q11-q36, which contains the SAMD9L gene, in 7 of 27 metaphase cells. She died of an unrelated cause at age 27 years. Their unaffected mother also carried the R986C mutation. All 3 individuals carried additional, but different, putative revertant variants in the SAMD9L gene (F1092L, R223X, R843W, Y568C, and E276X) that were demonstrated or predicted to abrogate the growth-suppressive properties of the R986C substitution. The authors postulated that the relatively mild clinical course in this family may have been due to the additional revertant SAMD9L variants or to a low level of monosomy 7. (less)