NM_005557.4(KRT16):c.379C>T (p.Arg127Cys) AND Palmoplantar keratoderma, nonepidermolytic, focal 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000015705.29

Allele description [Variation Report for NM_005557.4(KRT16):c.379C>T (p.Arg127Cys)]

NM_005557.4(KRT16):c.379C>T (p.Arg127Cys)

Gene:

KRT16:keratin 16 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_005557.4(KRT16):c.379C>T (p.Arg127Cys)

HGVS:

NC_000017.11:g.41612310G>A
NG_008301.1:g.5518C>T
NM_005557.4:c.379C>TMANE SELECT
NP_005548.2:p.Arg127Cys
NC_000017.10:g.39768562G>A
NM_005557.3:c.379C>T
P08779:p.Arg127Cys

Protein change:

R127C; ARG127CYS

Links:

UniProtKB: P08779#VAR_009184; OMIM: 148067.0002; dbSNP: rs59856285

NCBI 1000 Genomes Browser:

rs59856285

Molecular consequence:

NM_005557.4:c.379C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Palmoplantar keratoderma, nonepidermolytic, focal 1 (FNEPPK1)
Synonyms:: Palmoplantar keratoderma, nonepidermolytic, focal
Identifiers:: MONDO: MONDO:0013073; MedGen: C4552049; OMIM: 613000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035970	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2005)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8595410, 16250206 Stevens, H. P., Kelsell, D. P., Spurr, N. K., Bishop, D. T., Purkis, P. E., Griffiths, W. A. D., Rustin, M. H. A., Leigh, I. M. Keratin staining and linkage of non-epidermolytic focal palmoplantar keratoderma (PPK) to 17q. (Abstract) Brit. J. Derm. 131: 425, 1994.,
SCV005086187	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8595410, 22336941, 24611874, 25741868
SCV005368102	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 13, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035970

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2005)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Stevens, H. P., Kelsell, D. P., Spurr, N. K., Bishop, D. T., Purkis, P. E., Griffiths, W. A. D., Rustin, M. H. A., Leigh, I. M. Keratin staining and linkage of non-epidermolytic focal palmoplantar keratoderma (PPK) to 17q. (Abstract) Brit. J. Derm. 131: 425, 1994.,

SCV005086187

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005368102

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 13, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

The genetic basis of pachyonychia congenita.

Smith FJ, Liao H, Cassidy AJ, Stewart A, Hamill KJ, Wood P, Joval I, van Steensel MA, Björck E, Callif-Daley F, Pals G, Collins P, Leachman SA, Munro CS, McLean WH.

J Investig Dermatol Symp Proc. 2005 Oct;10(1):21-30. Review.

PubMed [citation]

PMID:: 16250206

Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families.

Shamsher MK, Navsaria HA, Stevens HP, Ratnavel RC, Purkis PE, Kelsell DP, McLean WH, Cook LJ, Griffiths WA, Gschmeissner S, et al.

Hum Mol Genet. 1995 Oct;4(10):1875-81.

PubMed [citation]

PMID:: 8595410

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000035970.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a 4-generation family with focal nonepidermolytic palmoplantar keratoderma (FNEPPK1; 613000), previously studied by Stevens et al. (1994), in which affected individuals also had follicular and orogenital hyperkeratosis, Shamsher et al. (1995) identified heterozygosity for an arg127-to-cys (R127C) substitution in the KRT16 gene at a highly conserved residue in the helix initiation motif of the 1A domain. The mutation was not found in unaffected family members or 20 controls. An alternative designation for this mutation is R10C.

In a sporadic patient with FNEPPK, Smith et al. (2005) identified heterozygosity for a c.379C-T transition in the KRT16 gene, resulting in the R127C substitution. The patient exhibited palmoplantar keratoderma without nail changes or oral lesions.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086187.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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, gain of function and dominant negative have been suggested (PMID: 22336941). (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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar, and has been observed in several families with pachyonychia congenita and palmoplantar keratoderma (PMIDs: 24611874, 8595410) (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been seen to segregate with disease in ten affected members of one family with palmoplantar keratoderma (PMID: 8595410). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV005368102.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PM5_STR,PS4_MOD,PM1,PP1,PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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