Submissions for variant NM_015166.4(MLC1):c.278C>T (p.Ser93Leu)

gnomAD frequency: 0.00001  dbSNP: rs80358245

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV000004979	SCV001193821	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2019-12-09	criteria provided, single submitter	clinical testing	NM_015166.3(MLC1):c.278C>T(S93L) is classified as likely pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 14615938, 11254442, 22006981 and 18757878. Classification of NM_015166.3(MLC1):c.278C>T(S93L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and the incidence of disease is extremely low. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380081	SCV001578024	pathogenic	not provided	2023-10-12	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 93 of the MLC1 protein (p.Ser93Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 12850517, 14615938, 25796299, 27081509, 27322623). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.393C>T. ClinVar contains an entry for this variant (Variation ID: 4714). 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 MLC1 protein function. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 22006981). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV001380081	SCV002502162	pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155016	SCV003845178	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: MLC1 c.278C>T (p.Ser93Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 234558 control chromosomes. c.278C>T has been reported in the literature in multiple individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (e.g. Shimada_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Duarri_2008, Ridder_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000004979	SCV004194975	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2024-03-27	criteria provided, single submitter	clinical testing
OMIM	RCV000004979	SCV000025155	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2003-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000004979	SCV000041277	not provided	Megalencephalic leukoencephalopathy with subcortical cysts 1		no assertion provided	literature only