ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Alopecia-neuroectodermal syndrome 4 (MIM#618840), cataract 44 (MIM#616509), hypotrichosis 14 (MIM#618275). (I) 0106 - This gene is associated with autosomal recessive disease. Pathogenic variants giving rise to ocular abnormalities are more likely to be in the C-terminal domain while pathogenic variants giving rise to hair loss are more likely to be in the N-terminal domain (PMIDs: 30401459, 33155697). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra and inter-familial variability have been reported with respect to epilepsy or brain anomaly (PMID: 30723320). (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable downstream truncating variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This frameshift has been observed in individual(s) with congenital hypotrichosis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs747990816, gnomAD 0.003%). This sequence change results in a frameshift in the LSS gene (p.Gly717Serfs*69). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the LSS protein and extend the protein by 52 additional amino acid residues.

Frameshift variant predicted to result in abnormal protein length as the last 16 amino acids are replaced with 39 different amino acids; Has not been previously published as pathogenic or benign to our knowledge