NM_015166.4(MLC1):c.274C>T (p.Pro92Ser) AND Megalencephalic leukoencephalopathy with subcortical cysts 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 29, 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:: RCV000004984.18

Allele description [Variation Report for NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)]

NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_015166.4(MLC1):c.274C>T (p.Pro92Ser)

HGVS:

NC_000022.11:g.50080391G>A
NG_009162.1:g.10539C>T
NM_001376472.1:c.274C>T
NM_001376473.1:c.274C>T
NM_001376474.1:c.274C>T
NM_001376475.1:c.274C>T
NM_001376476.1:c.274C>T
NM_001376477.1:c.274C>T
NM_001376478.1:c.274C>T
NM_001376479.1:c.274C>T
NM_001376480.1:c.184C>T
NM_001376481.1:c.274C>T
NM_001376482.1:c.267+2693C>T
NM_001376483.1:c.267+2693C>T
NM_001376484.1:c.37C>T
NM_015166.4:c.274C>TMANE SELECT
NM_139202.3:c.274C>T
NP_001363401.1:p.Pro92Ser
NP_001363402.1:p.Pro92Ser
NP_001363403.1:p.Pro92Ser
NP_001363404.1:p.Pro92Ser
NP_001363405.1:p.Pro92Ser
NP_001363406.1:p.Pro92Ser
NP_001363407.1:p.Pro92Ser
NP_001363408.1:p.Pro92Ser
NP_001363409.1:p.Pro62Ser
NP_001363410.1:p.Pro92Ser
NP_001363413.1:p.Pro13Ser
NP_055981.1:p.Pro92Ser
NP_055981.1:p.Pro92Ser
NP_631941.1:p.Pro92Ser
NC_000022.10:g.50518820G>A
NM_001376474.1:c.274C>T
NM_015166.3:c.274C>T
NR_164811.1:n.621C>T
NR_164812.1:n.405C>T
NR_164813.1:n.798C>T
Q15049:p.Pro92Ser

Protein change:

P13S; PRO92SER

Links:

UniProtKB: Q15049#VAR_017439; OMIM: 605908.0007; dbSNP: rs121908345

NCBI 1000 Genomes Browser:

rs121908345

Molecular consequence:

NM_001376482.1:c.267+2693C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001376483.1:c.267+2693C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001376472.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376473.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376474.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376475.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376476.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376477.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376478.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376479.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376480.1:c.184C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376481.1:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001376484.1:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015166.4:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139202.3:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164811.1:n.621C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164812.1:n.405C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164813.1:n.798C>T - 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
SCV000025160	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2002)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11935341, 11254442, 12189496
SCV000439243	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18757878, 11935341, 12189496, 16470554, 21145992 Citation Link,
SCV000485560	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 8, 2016)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18757878, 11935341, 12189496, 21145992, 16470554, 23793458, 22405205 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001529596	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002813874	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003798989	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801424	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (Hauer et al. (Genet Med. 2018))	Pathogenic (Mar 19, 2024)	germline	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	yes	2	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.

Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, Mejaski-Bosnjak V, van der Maarel SM, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS.

Am J Hum Genet. 2001 Apr;68(4):831-8. Epub 2001 Mar 6.

PubMed [citation]

PMID:: 11254442
PMCID:: PMC1275636

Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects.

Duarri A, Teijido O, López-Hernández T, Scheper GC, Barriere H, Boor I, Aguado F, Zorzano A, Palacín M, Martínez A, Lukacs GL, van der Knaap MS, Nunes V, Estévez R.

Hum Mol Genet. 2008 Dec 1;17(23):3728-39. doi: 10.1093/hmg/ddn269. Epub 2008 Aug 30.

PubMed [citation]

PMID:: 18757878
PMCID:: PMC2581428

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000025160.2

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

Description

In 3 unrelated families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), 2 from Croatia and 1 from U.K./Eastern Europe, Leegwater et al. (2002) found compound heterozygosity for mutations in the MLC1 gene, with 1 of the alleles carrying a pro92-to-ser (P92S) missense mutation. The amino acid change resulted from a C-to-T transition at nucleotide 274. In the U.K./Eastern Europe case, the second mutation was tyr198-to-ter (605908.0008), described by Leegwater et al. (2001).

In a family of mixed Jewish ancestry (the father a Libyan Jew and the mother an Ashkenazi Jew) with megalencephalic leukoencephalopathy with subcortical cysts, Ben-Zeev et al. (2002) identified the P92S substitution. The mutation was not found in 140 unaffected Ashkenazi control chromosomes.

#	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 Illumina Laboratory Services, Illumina, SCV000439243.3

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

Description

The MLC1 c.274C>T (p.Pro92Ser) missense variant has been identified in a compound heterozygous state in at least three individuals with megalencephalic leukoencephalopathy, in a heterozygous state in two affected individuals in whom a second variant was not identified, and in one affected individual in whom a second variant was found but zygosity was not confirmed (Leegwater et al. 2002; Ben-Zeev et al. 2002; Montagna et al. 2006; Yuzbasioglu et al. 2011). The p.Pro92Ser variant was absent from 240 control alleles and is reported at a frequency of 0.00037 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using HeLa and COS cells demonstrated reduced surface expression of the p.Pro92Ser-MLC1 protein compared to wild type. The variant protein was confined to late endosomes/lysosomes instead of recycling endosomes (Duarri et al. 2008). Based on the evidence, the p.Pro92Ser variant is classified as likely pathogenic for megalencephalic leukoencephalopathy with subcortical cysts. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Counsyl, SCV000485560.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Baylor Genetics, SCV001529596.2

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002813874.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003798989.2

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

Description

PS3, PM2, PP3

#	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		not provided	not provided	not provided	not provided

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV004801424.1

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

Description

This variant has been identified by standard clinical testing. in trans with MLC1 (NM_015166.4): c.423+1G>T

#	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		2	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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