ClinVar Genomic variation as it relates to human health

In 2 sibs, born of consanguineous Ashkenazi Jewish parents, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Srour et al. (2015) identified a homozygous c.766G-A transition (rs201278558) in the SLC1A4 gene, resulting in a glu256-to-lys (E256K) substitution at a highly conserved residue in the middle of the protein at the junction between its second intracellular loop and transmembrane domain 5. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Variant Server databases and 700 in-house exomes. The mutation segregated with the disorder in the family. The reported frequency in control databases was very low: 0.000077 in the Exome Variant Server, and 0.00017 in the ExAC database. It was found in heterozygous state in 5 of 540 Ashkenazi Jewish control individuals (allele frequency of 0.0056). Functional studies of the variant were not performed. Heimer et al. (2015) identified a homozygous E256K mutation in the SLC1A4 gene in a 4.5-year-old girl of Ashkenazi Jewish descent with SPATCCM. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated girl of Ashkenazi-Iraqi descent with the disorder was compound heterozygous for E256K and a 2-bp deletion (600229.0002), which the authors cited as c.945delTT, resulting in a frameshift and premature termination (Leu315HisfsTer42). The E256K mutation was found in 1 of 100 Ashkenazi Jewish controls, but was either absent or at very low frequency in other general population databases. Functional studies of the variants were not performed. Damseh et al. (2015) identified a homozygous E256K mutation in 9 patients from 7 unrelated families of Ashkenazi Jewish descent with SPATCCM. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Among 860 control individuals of Ashkenazi Jewish descent, 6 carried the variant (frequency of carriers in this population estimated to be 0.7%). The variant was also found in 21 of over 60,000 individuals in the ExAC database. Haplotype analysis indicated that the E256K mutation was a founder mutation in the Ashkenazi Jewish population. In vitro functional expression studies in HEK cells showed that L-serine and L-alanine transport by the E256K variant was reduced by 25% and 20%, respectively, compared to wildtype. Another patient, born of an Ashkenazi Jewish father and an Iraqi-Jewish mother, was compound heterozygous for the E256K mutation and a 2-bp deletion, c.944_945del (600229.0002), resulting in a frameshift and premature termination (Leu315fs). (less)