Submissions for variant NM_015166.4(MLC1):c.176G>A (p.Gly59Glu)

dbSNP: rs80358242

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000293896	SCV000329721	pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced expression of the protein at the plasma membrane and reduced protein stability (PMID: 18757878); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23793458, 22975760, 18757878, 12189496)
Myriad Genetics, Inc.	RCV000004986	SCV001194087	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2019-11-11	criteria provided, single submitter	clinical testing	NM_015166.3(MLC1):c.176G>A(G59E) is classified as likely pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 12189496, 23793458 and 18757878. Classification of NM_015166.3(MLC1):c.176G>A(G59E) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000293896	SCV001202219	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 59 of the MLC1 protein (p.Gly59Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy (PMID: 12189496). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4721). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 23793458). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000004986	SCV002811613	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2024-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001826418	SCV002819494	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: MLC1 c.176G>A (p.Gly59Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249342 control chromosomes. c.176G>A has been reported in the literature to segregate with disease in multiple homozygous individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (Ben-Zeev_2002). 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, demonstrating reduced expression of the protein in the plasma membrane and reduced protein stability (Duarri_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000004986	SCV004194978	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2024-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV000004986	SCV000025162	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2002-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000004986	SCV000041275	not provided	Megalencephalic leukoencephalopathy with subcortical cysts 1		no assertion provided	literature only
Natera, Inc.	RCV001826418	SCV002076191	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2020-10-28	no assertion criteria provided	clinical testing