Submissions for variant NM_015166.4(MLC1):c.959C>A (p.Thr320Lys)

dbSNP: rs281875313

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411937	SCV000486784	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2016-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411937	SCV004195011	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2022-09-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059749	SCV004300041	likely pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with MLC1-related conditions (PMID: 21555057, 31069529, 32209057). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 320 of the MLC1 protein (p.Thr320Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 68797). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689442	SCV005185082	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: MLC1 c.959C>A (p.Thr320Lys) 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 was absent in 245644 control chromosomes (gnomAD). c.959C>A has been reported in the literature in multiple homozygous individuals affected with megalencephalic leukoencephalopathy with subcortical cysts 1 and in several families, the variant segregated with the disease (examples: Boor_2006, Ilyas_2020, Shukla_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16652334, 32209057, 21555057). ClinVar contains an entry for this variant (Variation ID: 68797). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000411937	SCV005663891	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2024-05-22	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059749	SCV000091319	not provided	not provided		no assertion provided	not provided
Biological Sciences, International Islamic University, Islamabad	RCV000411937	SCV001167373	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2019-10-08	no assertion criteria provided	clinical testing	The mutation was identified after the exome Sequencing of the patient collected from Pakistan. Rare variants are filtered out with an allelic frequency of less than 1%. Only MLC1 gene mutation showing co-segregation with family.