Submissions for variant NM_007317.3(KIF22):c.443C>T (p.Pro148Leu)

dbSNP: rs193922921

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000288912	SCV000329964	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22152677, 25256152, 19277648, 22152678, 28229453, 30138938, 32860008, 27535533)
Fulgent Genetics, Fulgent Genetics	RCV000023269	SCV000894076	pathogenic	Spondyloepimetaphyseal dysplasia with multiple dislocations	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000023269	SCV001368665	likely pathogenic	Spondyloepimetaphyseal dysplasia with multiple dislocations	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
Centogene AG - the Rare Disease Company	RCV000023269	SCV001426590	pathogenic	Spondyloepimetaphyseal dysplasia with multiple dislocations		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001265811	SCV001443983	likely pathogenic	Inborn genetic diseases	2018-02-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000288912	SCV001832534	pathogenic	not provided	2021-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000288912	SCV002242158	pathogenic	not provided	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 148 of the KIF22 protein (p.Pro148Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spondyloepimetaphyseal dysplasia with joint laxity (PMID: 22152677, 22152678, 25256152). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30334). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF22 protein function. This variant disrupts the p.Pro148 amino acid residue in KIF22. Other variant(s) that disrupt this residue have been observed in individuals with KIF22-related conditions (PMID: 22152677), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000023269	SCV002512519	pathogenic	Spondyloepimetaphyseal dysplasia with multiple dislocations	2021-10-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP1 moderate, PP3 supporting
OMIM	RCV000023269	SCV000044560	pathogenic	Spondyloepimetaphyseal dysplasia with multiple dislocations	2011-12-09	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000023269	SCV000987047	pathogenic	Spondyloepimetaphyseal dysplasia with multiple dislocations	2014-09-26	no assertion criteria provided	literature only