rs587783772

Positions:

• chrX-150659665-G-A
• chrX-150659665-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000252.3(MTM1):​c.1262G>A​(p.Arg421Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,415 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Scores: Splicing: ADA: 0.9223
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.94

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-150659665-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 599006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-150659665-G-A is Pathogenic according to our data. Variant chrX-150659665-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 158914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150659665-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.1262G>A	p.Arg421Gln	missense_variant, splice_region_variant	12/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.1262G>A	p.Arg421Gln	missense_variant, splice_region_variant	12/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092415 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 358167

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000158914, PMID:9285787). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22520358, 9285787, 9305655, 11793470). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000599006, PMID:26338224). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.974>=0.6, 3CNET: 0.994>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MTM1 protein function (PMID: 23071445, 12646134, 23917616, 21135508, 17973976). This variant has been observed in individuals with myotubular myopathy (PMID: 22520358, 9285787, 9305655, 11793470, 10790201). ClinVar contains an entry for this variant (Variation ID: 158914). This variant is not present in population databases (rs587783772, ExAC no frequency). This sequence change replaces arginine with glutamine at codon 421 of the MTM1 protein (p.Arg421Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2017	The p.R421Q substitution has been reported in multiple individuals and has been reported previously as amaternally inherited variant in an individual with severe myotubular myopathy, and supportive histologicalfindings on muscle biopsy (Koga et al., 2012). Crystallography has shown that R421 is located within thephosphatase domain and functional studies showed that p.R421Q eliminated phosphatase activity (Goryunovet al., 2008). This substitution occurs at a position that is conserved across species, and multiple variants have been reported in nearby residues in association with myotubular myopathy (Stenson et al., 2009).Therefore, p.R421Q is considered a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

Spastic paraplegia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

-

- -

Congenital myopathy with fiber type disproportion Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS1+PS2+PM1+PM2+PP2+PP3+PP4+PP5 -

Centronuclear myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS1+PS2+PM1+PM2+PP2+PP3+PP4+PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Gain of ubiquitination at K417 (P = 0.0511);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.78
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: rs587783772; hg19: chrX-149828138; COSMIC: COSV60337210;