Submissions for variant NM_005857.5(ZMPSTE24):c.50del (p.Lys17fs)

dbSNP: rs281875360

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128743	SCV000581843	pathogenic	not provided	2017-05-05	criteria provided, single submitter	clinical testing	The c.50delA variant in the ZMPSTE24 gene has been reported previously in association with restrictive dermopathy when present in the homozygous state or when in trans with another loss-of-function variant (Smigiel et al., 2010; Navarro et al., 2014; Matuleviciene et al., 2016). The c.50delA variant causes a frameshift starting with codon Lysine 17, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Lys17SerfsX21. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.50delA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret c.50delA as a pathogenic variant.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000034313	SCV001950009	pathogenic	Lethal tight skin contracture syndrome	2021-08-11	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_005857.5:c.1085dup.
Invitae	RCV000128743	SCV002247278	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys17Serfs*21) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (PMID: 22718200, 24169522). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with restrictive dermopathy (PMID: 20101687, 26379196). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41411). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000034313	SCV000058264	pathogenic	Lethal tight skin contracture syndrome	2010-02-01	no assertion criteria provided	literature only
ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	RCV000128743	SCV000172383	not provided	not provided		no assertion provided	not provided