ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Identified as a maternally inherited variant in five hemizygous males with neurodevelopmental disorders from three unrelated families in the literature (Johnson et al., 2019), and in one family, the mother reportedly had seizures in childhood which resolved; Of the two isoforms of the USP9X gene, the long isoform is poorly expressed in male control fibroblasts compared to the short isoform, and this variant is located within exon 43 of the long isoform and within intron 43 of the short isoform (Johnson et al., 2019); Expression studies using patient-derived fibroblasts show that this variant causes loss of only the long isoform while overall levels of USP9X mRNA and protein remain similar to controls, suggesting USP9X mRNA and protein are still normally expressed from the short isoform (Johnson et al., 2019); however, further studies are needed to determine the clinical relevance of the long isoform and the role of differential isoform expression in gene function; Frameshift variant predicted to result in protein truncation or nonsense mediated decay for which loss-of-function in only the long isoform of the USP9X gene is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 27770309, 31443933)

The USP9X c.7440dupA variant is predicted to result in a frameshift and premature protein termination (p.Ala2481Serfs*17). This variant has been previously reported as maternally inherited and a variant of uncertain significance in three individuals with neurodevelopmental disorder (Table S4, Johnson et al. 2020. PubMed ID: 31443933). This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including four hemizygous alleles (http://gnomad.broadinstitute.org/variant/X-41089034-T-TA). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This sequence change creates a premature translational stop signal (p.Ala2481Serfs*17) in the USP9X gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in 5 males with neurodevelopmental disorders (PMID: 31443933, Invitae). ClinVar contains an entry for this variant (Variation ID: 423784). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant interpreted as Uncertain significance and reported on 06-15-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.