Submissions for variant NM_000424.4(KRT5):c.1649del (p.Gly550fs)

dbSNP: rs61126080

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056578	SCV000709814	pathogenic	not provided	2020-08-24	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein extension, replacing the last 41 amino acids with an elongated segment of 76 amino acids with different characteristics; Published functional studies demonstrates a damaging effect as in vitro expressed mutant K5 forms much shorter polymers with K14 than wildtype K5 with viscoelastic properties too weak to be reliably measured (Gu et al., 2005); In contrast to the typical hot spot mutations in KRT5 that affect the central rod domain, this variant is predicted to extend the tail domain of keratin 5 and completely alter its composition and physico-chemical properties; the extended tail region has been proposed to interfere with functional interactions between this keratin and its associated proteins (Gu et al., 2005); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20199538, 20055872, 27730678, 24104543, 23993914, 23889190, 15647384, 15982306, 28830826, 15324323, 12925204, 21375516, 32484238, 33274474)
Biomedical Innovation Departament, CIEMAT	RCV001352788	SCV001547418	pathogenic	Epidermolysis bullosa simplex	2009-01-06	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056578	SCV002179518	pathogenic	not provided	2024-03-16	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the KRT5 gene (p.Gly550Alafs*77). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the KRT5 protein and extend the protein by 35 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with autosomal dominant epidermolysis bullosa simplex (PMID: 12925204, 15324323, 24104543). 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: 14655). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects KRT5 function (PMID: 15647384). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000015761	SCV000036026	pathogenic	Epidermolysis bullosa simplex with migratory circinate erythema	2004-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000015761	SCV000040663	not provided	Epidermolysis bullosa simplex with migratory circinate erythema		no assertion provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056578	SCV000087690	not provided	not provided		flagged submission	not provided
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056578	SCV000087691	not provided	not provided		no assertion provided	not provided
OMIM	RCV001814959	SCV002061891	pathogenic	Epidermolysis bullosa simplex with mottled pigmentation	2004-09-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003894806	SCV004714245	pathogenic	KRT5-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The KRT5 c.1649delG variant is predicted to result in a frameshift and premature protein termination (p.Gly550Alafs*77). This variant is predicted to result in a frameshift and elongation of the protein beyond the normal stop codon (p.Gly550Alafs*77). This variant has been reported as a recurrent finding in individuals with epidermolysis bullosa simplex (see for example, Nagao-Watanabe et al. 2004. PubMed ID: 15324323; Kumagai et al. 2017. PubMed ID: 27730678; Table S1, Chen et al. 2020. PubMed ID: 32484238). It has been documented as a de novo variant, as well as inherited from a mosaic parent. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in KRT5 are expected to be pathogenic. This variant is interpreted as pathogenic.