rs281875317

Positions:

• chr22-50074296-C-G
• chr22-50074296-C-T

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000311597.10(MLC1):​c.634G>C​(p.Gly212Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G212E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLC1 ENST00000311597.10 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.90

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 24 ACMG points.

• PS1: Transcript ENST00000311597.10 (MLC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 68794
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50074295-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2737052.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 22-50074296-C-G is Pathogenic according to our data. Variant chr22-50074296-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.634G>C	p.Gly212Arg	missense_variant	8/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.634G>C	p.Gly212Arg	missense_variant	8/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.634G>C	p.Gly212Arg	missense_variant	8/12	1		ENSP00000379216	P1
MLC1	ENST00000442311.1	c.544G>C	p.Gly182Arg	missense_variant	7/8	5		ENSP00000401385
MLC1	ENST00000470008.1	n.114G>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 30, 2023	- -

Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 07, 2024

Variant summary: MLC1 c.634G>C (p.Gly212Arg) 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 250780 control chromosomes. c.634G>C has been reported in the literature in at least one biallelic individual affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (e.g. Duarri_2008). One publication reports experimental evidence evaluating an impact on protein function showing reduced expression of the MLC1 protein at the plasma membrane in vitro (e.g. Teijido_2004), however, does not allow convincing conclusions about the variant effect. A different variant resulting in the same amino acid change (c.634G>A, p.Gly212Arg) has been previously classified as Likely pathogenic by our lab. ClinVar contains an entry for this variant (Variation ID: 553381). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.96		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;
MVP		0.95
MPC		0.98
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs281875317; hg19: chr22-50512725;