NM_015166.4(MLC1):c.135dup (p.Cys46fs) AND Megalencephalic leukoencephalopathy with subcortical cysts 1

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Feb 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004987.19

Allele description [Variation Report for NM_015166.4(MLC1):c.135dup (p.Cys46fs)]

NM_015166.4(MLC1):c.135dup (p.Cys46fs)

Gene:

MLC1:modulator of VRAC current 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_015166.4(MLC1):c.135dup (p.Cys46fs)

HGVS:

NC_000022.11:g.50084773dup
NG_009162.1:g.6162dup
NM_001376472.1:c.135dup
NM_001376473.1:c.135dup
NM_001376474.1:c.135dup
NM_001376475.1:c.135dup
NM_001376476.1:c.135dup
NM_001376477.1:c.135dup
NM_001376478.1:c.135dup
NM_001376479.1:c.135dup
NM_001376480.1:c.135dup
NM_001376481.1:c.135dup
NM_001376482.1:c.135dup
NM_001376483.1:c.135dup
NM_001376484.1:c.-59+587dup
NM_015166.4:c.135dupMANE SELECT
NM_139202.3:c.135dup
NP_001363401.1:p.Cys46fs
NP_001363402.1:p.Cys46fs
NP_001363403.1:p.Cys46fs
NP_001363404.1:p.Cys46fs
NP_001363405.1:p.Cys46fs
NP_001363406.1:p.Cys46fs
NP_001363407.1:p.Cys46fs
NP_001363408.1:p.Cys46fs
NP_001363409.1:p.Cys46fs
NP_001363410.1:p.Cys46fs
NP_001363411.1:p.Cys46fs
NP_001363412.1:p.Cys46fs
NP_055981.1:p.Cys46fs
NP_055981.1:p.Cys46fs
NP_631941.1:p.Cys46fs
NC_000022.10:g.50523196_50523197insG
NC_000022.10:g.50523202dup
NM_015166.3:c.135dup
NM_015166.3:c.135dupC
NM_015166.4:c.135dupCMANE SELECT
NM_139202.3:c.135dupC
NR_164811.1:n.482dup
NR_164812.1:n.266dup
NR_164813.1:n.659dup

Protein change:

C46fs

Links:

OMIM: 605908.0011; dbSNP: rs80358241

NCBI 1000 Genomes Browser:

rs80358241

Molecular consequence:

NM_001376472.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376473.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376474.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376475.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376476.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376477.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376478.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376479.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376480.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376481.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376482.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376483.1:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015166.4:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_139202.3:c.135dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001376484.1:c.-59+587dup - intron variant - [Sequence Ontology: SO:0001627]
NR_164811.1:n.482dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164812.1:n.266dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164813.1:n.659dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1)
Synonyms:: Vacuolating megalencephalic leukoencephalopathy with subcortical cysts; Megalencephaly-cystic leukodystrophy; Leukoencephalopathy with swelling and cysts
Identifiers:: MONDO: MONDO:0024555; MedGen: C5779875; Orphanet: 2478; OMIM: 604004

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025163	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 12189496, 11935341
SCV000041274	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11935341, 14572144, 15037685
SCV001194053	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 13, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15037685, 14572144, 22006981, 12189496, 11935341 Citation Link,
SCV001573208	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003821540	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003925691	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21555057, 25741868
SCV004194971	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation.

Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, Hoffman EP, Naidu S.

Neurology. 2004 Mar 23;62(6):878-82.

PubMed [citation]

PMID:: 15037685

Megalencephalic leukoencephalopathy with subcortical cysts.

Singhal BS, Gorospe JR, Naidu S.

J Child Neurol. 2003 Sep;18(9):646-52. Review.

PubMed [citation]

PMID:: 14572144

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000025163.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a patient of Indian Agrawali ancestry with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Ben-Zeev et al. (2002) identified a homozygous insertion of a cytosine at nucleotide 135 at exon 2 of the MLC1 gene. This resulted in a frameshift and the creation of a stop codon 104 bp downstream.

Leegwater et al. (2002) described this mutation in 3 Agrawali patients. They stated that the disease was probably introduced into the tribe by a single founder, and the mutation is probably shared by all MLC patients of this community.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000041274.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194053.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, 22006981, 12189496 and 11935341. Classification of NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV001573208.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003821540.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003925691.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and and novel in 1KG, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease- causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 4722]. The observed variation has been previously reported in individuals with megalencephalic leukoencephalopathy (Shukla P, et.al., 2011). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004194971.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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