22-50064134-G-T

Variant names:

• chr22-50064134-G-T
• rs281875313
• NM_015166.4:c.959C>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 68797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50064134-G-T is described in Lovd as [Pathogenic]. Variant chr22-50064134-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLC1	NM_015166.4	c.959C>A	p.Thr320Lys	missense_variant	Exon 11 of 12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.959C>A	p.Thr320Lys	missense_variant	Exon 11 of 12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.959C>A	p.Thr320Lys	missense_variant	Exon 11 of 12	1		ENSP00000379216.2
MLC1	ENST00000483836.1	n.316C>A		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457136 Hom.: 0 Cov.: 39 AF XY: 0.00000276 AC XY: 2 AN XY: 725098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:4

Aug 09, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2022

Baylor 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. -

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other: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	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	.;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.69	T
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	D
GERP RS		4.0
Varity_R		0.24
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs281875313; hg19: chr22-50502563;