Submissions for variant NM_147191.1(MMP21):c.1372C>T (p.Arg458Ter)

gnomAD frequency: 0.00016  dbSNP: rs145119918

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255181	SCV000322069	likely pathogenic	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Identified in trans with a second MMP21 variant in a patient with heterotaxy in published literature (Westphal et al., 2019); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 112 amino acids are lost, and other loss-of-function variants have been reported downstream in the published literature.; This variant is associated with the following publications: (PMID: 31980526, 26437028, 33726816, 30868567)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826118	SCV000967626	likely pathogenic	Visceral heterotaxy	2018-12-13	criteria provided, single submitter	clinical testing	The p.Arg458X variant in MMP21 has been identified in the compound heterozygous state with another variant in MMP21 in one individual with heterotaxy (GeneDx pe rs. comm.) and in the heterozygous state in 2 individuals with heterotaxy (Guimi er 20115). It has also been identified in 0.03% (38/128942) of European chromoso mes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. This nonsense variant leads to a premature ter mination codon at position 458. This alteration occurs within the terminal 50 ba ses of the second to last exon and is, therefore, predicted to escape nonsense m ediated decay (NMD) and result in a truncated protein. Please note, additional t runcating variants downstream of this variant have been reported in the compound heterozygous state in individuals with heterotaxy and biallelic loss of functio n of MMP21 is been strongly associated with heterotaxy. In summary, although add itional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for heterotaxy in a n autosomal recessive manner. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Suppor ting, PM3_Supporting.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV001254033	SCV001429932	pathogenic	Heterotaxy, visceral, 7, autosomal	2017-06-07	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255181	SCV001905672	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001254033	SCV002023493	likely pathogenic	Heterotaxy, visceral, 7, autosomal	2020-05-30	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255181	SCV001744834	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000255181	SCV001797468	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255181	SCV001978138	pathogenic	not provided		no assertion criteria provided	clinical testing