rs781933660

Positions:

• chrX-150657977-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000252.3(MTM1):​c.1210G>A​(p.Glu404Lys) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E404D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.78

Genes affected

MTM1 (HGNC:7448): (myotubularin 1) This gene encodes a dual-specificity phosphatase that acts on both phosphotyrosine and phosphoserine. It is required for muscle cell differentiation and mutations in this gene have been identified as being responsible for X-linked myotubular myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-150657979-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 841786.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant X-150657977-G-A is Pathogenic according to our data. Variant chrX-150657977-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150657977-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.1210G>A	p.Glu404Lys	missense_variant	11/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.1210G>A	p.Glu404Lys	missense_variant	11/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jul 30, 2024	The variant is not observed in the gnomAD v4.0.0 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 12118066). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.76 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MTM1-related disorder (ClinVar ID: VCV000530855 / PMID: 9285787). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12118066, 17005396, 19084976, 25957634, 9285787). A different missense change at the same codon (p.Glu404Asp) has been reported to be associated with MTM1-related disorder (ClinVar ID: VCV000841786). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2023	Variant summary: MTM1 c.1210G>A (p.Glu404Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 182729 control chromosomes (gnomAD). c.1210G>A has been reported in the literature in multiple individuals affected with X-Linked Myotubular Myopathy (de Gouyon_1997, Hoffjan_2006, Fattori_2015, Rinnenthal_2018, Gangfuss_2021, Reumers_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant produced unstable proteins (Laporte_2002). The following publications have been ascertained in the context of this evaluation (PMID: 25957634, 33164942, 17005396, 10790201, 12118066, 34463354, 34011573, 30149909, 10063835, 9285787). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 404 of the MTM1 protein (p.Glu404Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked myotubular myopathy or centronuclear myopathy (PMID: 9285787, 12118066, 17005396, 19084976, 25957634). This variant is also known as c.1264G>A/ p.Glu404Lys. ClinVar contains an entry for this variant (Variation ID: 530855). 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 expected to disrupt MTM1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MTM1 function (PMID: 12118066). For these reasons, this variant has been classified as Pathogenic. -

Qualitative or quantitative defects of myotubularin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 25, 2023

The hemizygous p.Glu404Lys variant in MTM1 was identified by our study in one individual with X-linked myotubular myopathy 1. The p.Glu404Lys variant in MTM1 has been reported in six hemizygous individuals with X-linked myotubular myopathy 1 (PMID: 33164942, PMID: 9285787, PMID: 25957634, PMID: 17005396, PMID: 19084976, PMID: 34463354) and segregated with disease in four affected relatives from two families (PMID: 34463354, PMID: 17005396). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 530855) and has been interpreted as pathogenic by Invitae. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked myotubular myopathy 1. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.013	D
Sift4G	Benign	0.15	T
Polyphen		0.94	P
Vest4		0.89
MutPred		0.81		Gain of MoRF binding (P = 0.0206);
MVP		0.98
MPC		0.81
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781933660; hg19: chrX-149826450; COSMIC: COSV60336339;