NM_015166.4:c.959C>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_015166.4(MLC1):c.959C>A(p.Thr320Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,136 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T320M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 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: 2.04

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

megalencephalic leukoencephalopathy with subcortical cysts 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Myriad Women’s Health
megalencephalic leukoencephalopathy with subcortical cysts
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MLC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 22-50064134-G-T is Pathogenic according to our data. Variant chr22-50064134-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4 link	c.959C>A	p.Thr320Lys	missense_variant	Exon 11 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.959C>A	p.Thr320Lys	missense_variant	Exon 11 of 12	1	NM_015166.4	ENSP00000310375.6	Q15049-1
MLC1	ENST00000395876.6 link	c.959C>A	p.Thr320Lys	missense_variant	Exon 11 of 12	1		ENSP00000379216.2	Q15049-1
MLC1	ENST00000483836.1 link	n.316C>A		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457136

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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:4

Aug 09, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 03, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 08, 2019

Biological Sciences, International Islamic University, Islamabad

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method: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. -

not provided

Pathogenic:1Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 68797). This missense change has been observed in individual(s) with MLC1-related conditions (PMID: 21555057, 31069529, 32209057). This variant is not present in population databases (gnomAD no frequency). 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). -

Megalencephalic leukoencephalopathy with subcortical cysts

Pathogenic:1

May 22, 2024

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.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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.82

.;T

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

2.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;D

Vest4

0.84

MutPred

0.88

Gain of ubiquitination at T320 (P = 0.0238);Gain of ubiquitination at T320 (P = 0.0238);

MVP

0.91

MPC

0.98

ClinPred

0.97

GERP RS

4.0

Varity_R

0.24

gMVP

0.54

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over