Submissions for variant NM_005857.5(ZMPSTE24):c.951_954+2del

dbSNP: rs747563189

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000293484	SCV000357429	uncertain significance	Mandibuloacral dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000329774	SCV000357430	uncertain significance	Lethal tight skin contracture syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000597416	SCV000701045	uncertain significance	not provided	2015-12-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000597416	SCV002017963	likely pathogenic	not provided	2020-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV000597416	SCV002300342	likely pathogenic	not provided	2021-07-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004543174	SCV004778291	uncertain significance	ZMPSTE24-related disorder	2023-11-28	criteria provided, single submitter	clinical testing	The ZMPSTE24 c.951_954+2del6 variant is predicted to result in a deletion affecting a canonical splice site. This deletion encompassed the last four nucleotides of exon 7 as well as the consensus splice site, and is expected to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Molecular Genetics, Royal Melbourne Hospital	RCV003993922	SCV004812643	uncertain significance	Mandibuloacral dysplasia with type B lipodystrophy	2023-05-04	criteria provided, single submitter	clinical testing	This sequence change in ZMPSTE24 occurs within the canonical splice donor site (+ 1,2) of intron 7. It is predicted to cause cryptic donor activation leading to an in-frame deletion (removes amino acids 317-318) that is expected to escape nonsense-mediated decay and remove <10% of the protein. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.036% (9/24,962 alleles) in the African/African American population, which is consistent with recessive disease. To our knowledge, this variant has not been previously reported in the relevant scientific literature and has been reported as a variant of uncertain significance and likely pathogenic (ClinVar ID: 297263). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PVS1_Moderate, PMS2_Supporting.