Submissions for variant NM_001168338.1(PLG):c.112A>G (p.Lys38Glu) (rs73015965)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000725124	SCV000334292	pathogenic	not provided	2018-09-06	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University	RCV000014551	SCV000538055	pathogenic	Plasminogen deficiency, type I	2016-01-27	criteria provided, single submitter	clinical testing	The c.112A>G (p.Lys38Glu) missense variant in the PLG gene has been previously reported in numerous affected individuals with autosomal recessive Plasminogen Deficiency and has been shown to segregate with disease in affected family members (Schuster et al., 1999; Schuster et al., 2001). This variant has been observed in affected individuals in trans with multiple variants (Cys122Ter, Arg134Lys, Arg513His, Arg216His, and Leu128Pro) (Schuster et al., 1999; Schuster et al., 2001). Functional studies have shown this variant causes decreased serum plasminogen activity and decreased plasminogen antigen levels (Schuster et al., 1999; Schuster et al., 2001; Tefs et al., 2006). Case-control studies have found this variant to be significantly more prevalent in affected individuals relative to controls (Tefs et al., 2006). This c.112A>G has been reported in the three population databases at a frequency lower than the prevalence of the disease (Exome Sequencing Project [ESP] = 0.616%, 1000 Genomes = 1%, and ExAC = 0.496%). The PLG gene is the only gene in which mutations are known to cause Plasminogen Deficiency. Therefore, this collective evidence supports the classification of the c.112A>G (p.Lys38Glu) as a recessive Pathogenic variant for Plasminogen Deficiency.
Fulgent Genetics,Fulgent Genetics	RCV000014551	SCV000893704	pathogenic	Plasminogen deficiency, type I	2018-10-31	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000014551	SCV000899298	likely pathogenic	Plasminogen deficiency, type I	2019-02-01	criteria provided, single submitter	research
OMIM	RCV000014551	SCV000034802	pathogenic	Plasminogen deficiency, type I	2006-11-01	no assertion criteria provided	literature only
Santos-Cortez Lab,University of Colorado School of Medicine	RCV000999694	SCV000996503	benign	Otitis media, susceptibility to	2019-07-26	no assertion criteria provided	research
Reproductive Health Research and Development,BGI Genomics	RCV000014551	SCV001142366	pathogenic	Plasminogen deficiency, type I	2020-01-06	no assertion criteria provided	curation	NM_000301.3:c.112A>G in the PLG gene has an allele frequency of 0.005 in European (non-Finnish) subpopulation in the gnomAD database. This variant has been observed in affected individuals in trans with multiple variants (Cys122Ter, Arg134Lys, Arg513His, Arg216His, and Leu128Pro) (PMID: 10233898; 12850227). Functional studies have shown this variant causes decreased serum plasminogen activity and decreased plasminogen antigen levels (PMID: 16849641). Case-control studies have found this variant to be significantly more prevalent in affected individuals relative to controls (PMID: 16849641). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PS4; PP4.