ClinVar

Description

Variant summary: SHH c.1040C>T (p.Pro347Leu) results in a non-conservative amino acid change located in the Hint domain (IPR001767) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 130974 control chromosomes (gnomAD). c.1040C>T has been reported in the literature in an individual affected with holoprosencephaly (Roessler_2009, Mercier_2011), and further information submitted to ClinVar from this lab (Muenke lab, National Institutes of Health) has indicated that this was a de novo occurrence. These data suggest that the variant may be associated with holoprosencephaly, a SHH-Related Disorder. A study examining the variant in a zebrafish model found that unlike the wild-type protein, Pro347Leu was unable to rescue the null phenotype, indicating that it impairs protein function. Furthermore, other variants which affect the same residue (e.g. P347R, P347Q) have also been reported in holoproencephaly patients (Roessler_2009, HGMD database). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.