Submissions for variant NM_020738.4(KIDINS220):c.4417dup (p.Leu1473fs)

dbSNP: rs34141362

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008839	SCV001168643	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 299 amino acids are lost and replaced with 5 incorrect amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
AiLife Diagnostics, AiLife Diagnostics	RCV001008839	SCV002502940	likely pathogenic	not provided	2020-05-05	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225957	SCV003922180	likely pathogenic	Spastic paraplegia, intellectual disability, nystagmus, and obesity	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Leu1473ProfsTer6 variant in KIDINS220 was identified by our study in one individual with strabismus, facial tics, seizures, global developmental delay, cortical dysplasia, and partial agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Leu1473ProfsTer6 variant in KIDINS220 has not been previously reported in the literature in individuals with spastic paraplegia, intellectual disability, nystagmus, and obesity. This variant has also been reported in ClinVar (Variation ID: 817641) and has been interpreted as pathogenic by GeneDx and as likely pathogenic by AiLife Diagnostics. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1473 and leads to a premature termination codon 6 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the KIDINS220 gene is an established disease mechanism in autosomal dominant spastic paraplegia, intellectual disability, nystagmus, and obesity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant spastic paraplegia, intellectual disability, nystagmus, and obesity. ACMG/AMP Criteria applied: PVS1_Strong, PS2_Supporting, PM2_Supporting (Richards 2015).