Description
The S331Y pathogenic variant in the SPTLC1 gene has been reported previously as a heterozygous de novo variant in an individual with a diagnosis of HSN1A who presented with normal early development followed by failure to thrive in childhood, abnormal gait, frequent falls, and moderate hand tremor. Later in childhood, general muscle hypotrophy and hypotonia with pronounced limb weakness, growth retardation, fasciculations, joint hypermobility, juvenile cataracts, foot burns and scars and prominent sensory disturbances were noted (Auer-Grumbach et al., 2013). The S331Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S331Y variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies show a significant reduction in the canonical SPT activity and a significant increase of 1-deoxy-sphinganin formation in HEK293 cells compared to wild type cells (Auer-Grumbach et al., 2013; Bode et al., 2016). A missense variant at the same residue (S331F) has also been reported in multiple individuals with severe and early onset HSN1A (Rotthier et al., 2011; Rotthier et al., 2009). Therefore, we interpret S331Y as a pathogenic variant.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
