22-50068503-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_015166.4(MLC1):​c.824C>A​(p.Ala275Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,598 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A275T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MLC1
NM_015166.4 missense

Scores

7
10
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.66

Publications

6 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_015166.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-50068504-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 836275.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 22-50068503-G-T is Pathogenic according to our data. Variant chr22-50068503-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 554164.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
MLC1NM_015166.4 linkc.824C>A p.Ala275Asp missense_variant Exon 10 of 12 ENST00000311597.10 NP_055981.1 Q15049-1A0A024R4V4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLC1ENST00000311597.10 linkc.824C>A p.Ala275Asp missense_variant Exon 10 of 12 1 NM_015166.4 ENSP00000310375.6 Q15049-1
MLC1ENST00000395876.6 linkc.824C>A p.Ala275Asp missense_variant Exon 10 of 12 1 ENSP00000379216.2 Q15049-1
MLC1ENST00000483836.1 linkn.181C>A non_coding_transcript_exon_variant Exon 3 of 5 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251486
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461598
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727116
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111826
Other (OTH)
AF:
0.00
AC:
0
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:2Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Sep 27, 2017
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. -

Feb 20, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
Jan 07, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as 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: 554164). This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 25796299, 27081509, 28840990). 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 present in population databases (rs764669598, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 275 of the MLC1 protein (p.Ala275Asp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.49
T;T
Eigen
Uncertain
0.24
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.92
.;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.3
M;M
PhyloP100
8.7
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.2
D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
1.0
D;D
Vest4
0.99
MutPred
0.90
Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP
0.93
MPC
1.1
ClinPred
0.99
D
GERP RS
3.6
Varity_R
0.82
gMVP
0.93
Mutation Taster
=3/97
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs764669598; hg19: chr22-50506932; COSMIC: COSV61119101; COSMIC: COSV61119101; API