Submissions for variant NM_000226.4(KRT9):c.487C>T (p.Arg163Trp)

dbSNP: rs59616921

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056465	SCV000321849	pathogenic	not provided	2020-10-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Located within the helix initiation motif within the 1A region of the rod domain, which is a well-known mutation hotspot intolerant to change; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19223272, 25299193, 23278372, 7512862, 22262370, 27864007, 30666268, 15564199, 10844507)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626629	SCV000747330	likely pathogenic	Palmoplantar keratoderma	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000003132	SCV000894118	pathogenic	Epidermolytic palmoplantar keratoderma	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000056465	SCV001371122	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000003132	SCV002498673	pathogenic	Epidermolytic palmoplantar keratoderma	2021-08-10	criteria provided, single submitter	clinical testing	This sequence change in KRT9 is predicted to replace arginine with tryptophan at codon 163 (p.(Arg163Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is an invariant residue in human type 1 keratins in the coil 1A alpha-helical segment of the intermediate filament rod domain (PMID: 7512862). There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with epidermolytic palmoplantar keratoderma, and segregates with the disease in multiple families (PMID: 7512862, 7523529). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP3.
Invitae	RCV000056465	SCV003441882	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2997). This missense change has been observed in individuals with epidermolytic palmoplantar keratoderma (PMID: 22262370). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 163 of the KRT9 protein (p.Arg163Trp). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRT9 protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003132	SCV004027777	pathogenic	Epidermolytic palmoplantar keratoderma	2023-05-19	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PP1_STR,PS4_MOD,PM1,PM2_SUP,PP3
OMIM	RCV000003132	SCV000023290	pathogenic	Epidermolytic palmoplantar keratoderma	2009-03-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056465	SCV000087574	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000056465	SCV001744854	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000056465	SCV001956833	pathogenic	not provided		no assertion criteria provided	clinical testing