ClinVar Miner

Submissions for variant NM_005557.4(KRT16):c.395T>C (p.Leu132Pro) (rs60944949)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057042 SCV000321825 pathogenic not provided 2016-01-29 criteria provided, single submitter clinical testing The L132P variant has been published previously in association with pachyonychia congenita (McLean et al., 1995; Wilson et al., 2014; Smith et al., 2005; Dai et al., 2014). It was not observed in approximately 6,400 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 L132P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within a known hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with pachyonychia congenita have been reported in nearby residues (R127C/S/G/H/P, L128Q/P) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene mutations affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in hyperkeratosis (Chamcheu et al., 2011). Therefore, we consider L132P to be pathogenic.
OMIM RCV000015704 SCV000035969 pathogenic Pachyonychia congenita 1 2005-10-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057042 SCV000088155 not provided not provided no assertion provided not provided

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