Submissions for variant NM_000301.5(PLG):c.112A>G (p.Lys38Glu)

gnomAD frequency: 0.00282  dbSNP: rs73015965

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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
Mayo Clinic Laboratories, Mayo Clinic	RCV000725124	SCV001713388	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000725124	SCV001751572	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as K19E using alternate nomenclature; This variant is associated with the following publications: (PMID: 22995991, 27976734, 28876531, 20981092, 10233898, 30487145, 12850227, 26340456, 12945885, 23629776, 15269832, 16849641, 31980526, 31589614, 12876630, 34426522)
Revvity Omics, Revvity	RCV000725124	SCV002018859	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002221996	SCV002499605	uncertain significance	Deep venous thrombosis		criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000725124	SCV002501229	likely pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000014551	SCV002518881	pathogenic	Plasminogen deficiency, type I	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725124	SCV003259111	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 38 of the PLG protein (p.Lys38Glu). This variant is present in population databases (rs73015965, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with plasminogen deficiency and ligneous conjunctivitis (PMID: 10233898, 15269832, 16849641, 23629776, 26340456, 27976734). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLG protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000014551	SCV004013023	uncertain significance	Plasminogen deficiency, type I		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014551	SCV004241800	pathogenic	Plasminogen deficiency, type I	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: PLG c.112A>G (p.Lys38Glu) results in a conservative amino acid change located in the PAN/Apple domain (IPR003609) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251130 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PLG causing Plasminogen Deficiency phenotype (0.0011), suggesting that the variant could be benign. However, c.112A>G has been reported in the literature as a biallelic genotype in many individuals affected with Plasminogen Deficiency/Ligneous Conjuctivitis, including cases where it has been found in trans with loss of function variants and it has been found to segregate with disease in multiple unrelated families (e.g. Schuster_1999, Tefs_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the secretion kinetics of the variant were normal, however, this study did not directly assess PLG activity (Tefs_2006). The following publications have been ascertained in the context of this evaluation (PMID: 10233898, 16849641). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Ten submitters classified the variant as pathogenic/likely pathogenic, one submitter classified it as uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as pathogenic.
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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000725124	SCV001553780	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The PLG p.Lys38Glu variant was found in 13 families in Scotland who were identified to have type I plasminogen deficiency (hypoplasminogenaemia) upon donating blood; the variant was reported to be the most common cause of hypoplasminogenaemia in Scotland, with a prevalence of 0.14% (Tefs_2003_PMID:12945885). Three unrelated patients with ligneous conjunctivitis were found to be compound heterozygous for the p.K38E variant; two of these patients presented in infancy while the third patient did not present until age 69. The two patients presenting in infancy both inherited the p.K38E variant from their unaffected fathers. Plasminogen antigen and activity levels were tested in these patients as well as their families; all three compound heterozygous patients with the p.K38E variant had little to no plasminogen antigen or activity, and the two p.K38E heterozygous carriers had decreased activity compared to wildtype (Schuster_1999_PMID:10233898). The variant was identified in dbSNP (ID: rs73015965), ClinVar (classified as pathogenic by Fulgent Genetics, EGL Genetics and Knight Diagnostic Laboratories, Oregon Health and Sciences University and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge) and LOVD 3.0 (classified as a VUS and pathogenic). The variant was identified in control databases in 817 of 282530 chromosomes (4 homozygous) at a frequency of 0.002892 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 645 of 128850 chromosomes (freq: 0.005006), Other in 24 of 7220 chromosomes (freq: 0.003324), Latino in 99 of 35438 chromosomes (freq: 0.002794), African in 34 of 24962 chromosomes (freq: 0.001362), European (Finnish) in 13 of 25122 chromosomes (freq: 0.000518) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Lys38 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One study identified 6 type I plasminogen deficiency patients with homozygous K38E mutations that had a milder clinical course and higher residual plasminogen antigen and activity levels than patients with other plasminogen mutations; a homozygous K38E mutation (and similarly decreased PLG values) was also found in one patient's healthy brother, suggesting incomplete penetrance (Tefs_2006_PMID:16849641). Functional in vitro data determined that secretion of mutant K38E protein from transfected cells was not significantly reduced (Tefs_2006_PMID:16849641). In summary, this variant is considered a hypomorphic allele and in combination with other variants in cis or trans, may result in reduced enzyme activity. Based on the above information this variant meets our laboratory’s criteria to be classified as likely pathogenic.