Submissions for variant NM_015166.4(MLC1):c.206C>T (p.Ser69Leu)

gnomAD frequency: 0.00001  dbSNP: rs281875309

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biochemistry Laboratory of CDMU, Chengde Medical University	RCV000024319	SCV000899199	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1		criteria provided, single submitter	case-control
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059741	SCV001233598	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 69 of the MLC1 protein (p.Ser69Leu). This variant is present in population databases (rs281875309, gnomAD 0.01%). This missense change has been observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 21145992, 21160490, 21624973). ClinVar contains an entry for this variant (Variation ID: 31622). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLC1 protein function. Experimental studies have shown that this missense change affects MLC1 function (PMID: 21624973, 22416245). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000024319	SCV004194982	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2024-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001826507	SCV004240796	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: MLC1 c.206C>T (p.Ser69Leu) 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. The variant allele was found at a frequency of 2.8e-05 in 251294 control chromosomes. c.206C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (e.g. Yuzbasioglu_2011, Lopez-Hernandez_2011, Wang_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing reduced or negligible MLC1 protein product in vitro and in vivo in post-mortem brain lysates (Lopez-Hernandez_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21624973, 21160490, 21145992). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000024319	SCV000045610	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2011-08-15	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059741	SCV000091311	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001826507	SCV002076190	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2021-03-23	no assertion criteria provided	clinical testing