rs80358245

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_015166.4(MLC1):c.278C>T(p.Ser93Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,605,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S93S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

MLC1
NM_015166.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 7.19

Variant links:

Genes affected

MLC1 (HGNC:17082): (modulator of VRAC current 1) The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MLC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 22-50080387-G-A is Pathogenic according to our data. Variant chr22-50080387-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50080387-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4 link	c.278C>T	p.Ser93Leu	missense_variant	Exon 4 of 12	ENST00000311597.10	NP_055981.1	Q15049-1A0A024R4V4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MLC1	ENST00000311597.10 link	c.278C>T	p.Ser93Leu	missense_variant	Exon 4 of 12	1	NM_015166.4	ENSP00000310375.6	Q15049-1
MLC1	ENST00000395876.6 link	c.278C>T	p.Ser93Leu	missense_variant	Exon 4 of 12	1		ENSP00000379216.2	Q15049-1
MLC1	ENST00000442311.1 link	c.188C>T	p.Ser63Leu	missense_variant	Exon 3 of 8	5		ENSP00000401385.1	A6PVC3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000171

AC:

AN:

234558

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

126654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000491

Gnomad NFE exome

AF:

0.0000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000241

AC:

AN:

1452924

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

721916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000357

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.00000722

Gnomad4 OTH exome

AF:

0.0000666

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jul 22, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Megalencephalic leukoencephalopathy with subcortical cysts

Pathogenic:1

Feb 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.88

MutPred

0.80

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;

MVP

0.91

MPC

0.77

ClinPred

0.96

GERP RS

5.3

Varity_R

0.55

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over