Submissions for variant NM_000422.3(KRT17):c.281G>A (p.Arg94His)

dbSNP: rs28928897

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000056515	SCV001250280	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015692	SCV002768338	pathogenic	Steatocystoma multiplex	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However in keratin proteins, missense at the start and end of the a-helical rod domain (within 1A and 2B) within the helix boundary motif domains are expected to interfere with assembly of intermediate filaments (PMIDs: 24611874, 14714564). In addition, induction of keratin K17 expression has been reported in psoriasis (PMID: 29784039). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located in the coil 1A region within the rod domain (PMID: 29784039), where reported missense variants are clustered (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with steatocystoma multiplex or pachyonychia congenita 2 (PMIDs: 9008238, 11886499, 19470054). It has also been reported as pathogenic once in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002496374	SCV002809853	likely pathogenic	Pachyonychia congenita 2; Steatocystoma multiplex	2021-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056515	SCV004297770	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the KRT17 protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Steatocystoma multiple (PMID: 9008238). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14590). 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) has been performed at Invitae 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 KRT17 protein function. This variant disrupts the p.Arg94 amino acid residue in KRT17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9767294, 25946540, 26165312, 29218738). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000015692	SCV000035957	pathogenic	Steatocystoma multiplex	2001-12-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056515	SCV000087626	not provided	not provided		no assertion provided	not provided
OMIM	RCV000114414	SCV000148346	pathogenic	Pachyonychia congenita 2	2001-12-01	no assertion criteria provided	literature only