Submissions for variant NM_000424.4(KRT5):c.980T>C (p.Met327Thr)

dbSNP: rs58072617

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056651	SCV000321835	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate shorter and less uniform K5 and K14 filaments (Chan et al., 1994); Located in the L12 linker region hotspot region that is intolerant to change (Bchetnia et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12101866, 21877134, 35247839, 33960018, 7520042, 8807337, 20199538)
Fulgent Genetics, Fulgent Genetics	RCV000762900	SCV000893309	pathogenic	Epidermolysis bullosa simplex with migratory circinate erythema; Epidermolysis bullosa simplex with mottled pigmentation; Epidermolysis bullosa simplex 1A, generalized severe; Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive; Epidermolysis bullosa simplex, Koebner type; Epidermolysis bullosa simplex 1C, localized; Dowling-Degos disease 1	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197083	SCV001367719	pathogenic	Epidermolysis bullosa simplex, Koebner type	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056651	SCV005836028	pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 327 of the KRT5 protein (p.Met327Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Weber-Cockayne epidermolysis bullosa simplex (PMID: 7520042). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14641). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KRT5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KRT5 function (PMID: 7520042). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV001731292	SCV000036012	pathogenic	Epidermolysis bullosa simplex 2C, localized	1996-01-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056651	SCV000087764	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003894805	SCV004713227	likely pathogenic	KRT5-related disorder	2024-02-20	no assertion criteria provided	clinical testing	The KRT5 c.980T>C variant is predicted to result in the amino acid substitution p.Met327Thr. This variant has been reported to segregate with autosomal dominant epidermolysis bullosa simplex in multiple individuals from two large family cohorts (Figure 2, Chan et al. 1994. PubMed ID: 7520042; Figure 1, Humphries et al. 1996. PubMed ID: 8807337). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as likely pathogenic.