ClinVar Miner

Submissions for variant NM_000424.4(KRT5):c.527A>G (p.Asn176Ser)

dbSNP: rs59092197
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000056609 SCV002588265 pathogenic not provided 2022-10-24 criteria provided, single submitter clinical testing Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011); Multiple pathogenic missense variants at this residue (p.(N176Y), p.(N176D), and p.(N176K)) have been reported in association with epidermolysis bullosa simplex at GeneDx and in published literature (Mariath et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27868258, 9036937, 20199538, 16882168, 9989794, 29932457, 32351751, 33822359, 31001817, 30286183, 29242947, 21176769)
3billion RCV003152677 SCV003841523 likely pathogenic Epidermolysis bullosa simplex with mottled pigmentation 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KRT5-related disorder (PMID: 9036937). However, the evidence of pathogenicity is insufficient at this time. A different missense change at the same codon (p.Asn176Lys) has been reported to be associated with KRT5 related disorder (PMID: 31001817). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056609 SCV000087722 not provided not provided no assertion provided not provided

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