rs111033178

Positions:

chr11-77190108-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000260.4(MYO7A):c.3719G>A(p.Arg1240Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,575,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R1240W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 9.43

Variant links:

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a domain MyTH4 1 (size 236) in uniprot entity MYO7A_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_000260.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-77190107-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.817

PP5

Variant 11-77190108-G-A is Pathogenic according to our data. Variant chr11-77190108-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 43218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77190108-G-A is described in Lovd as [Pathogenic]. Variant chr11-77190108-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-77190108-G-A is described in Lovd as [Pathogenic]. Variant chr11-77190108-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.3719G>A	p.Arg1240Gln	missense_variant	29/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.3719G>A	p.Arg1240Gln	missense_variant	29/49	1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000747

AC:

AN:

187292

Hom.:

AF XY:

0.000109

AC XY:

AN XY:

100916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000998

AC:

142

AN:

1422802

Hom.:

Cov.:

AF XY:

0.0000923

AC XY:

AN XY:

704020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000516

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000885

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000110

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1240 of the MYO7A protein (p.Arg1240Gln). This variant is present in population databases (rs111033178, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 15043528, 16652077, 17361009, 18463160, 20513143, 21569298, 21873662, 22135276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43218). 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 MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1240 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 24199935), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18463160, 16679490, 20513143, 21436283, 19683999, 25468891, 16652077, 16400615, 17361009, 27068579, 28559085, 10094549, 10930322, 15043528, 21569298, 16963483, 26969326, 22135276, 15221449, 9354784, 28041643, 31479088, 31980526, 32581362, 31589614, 32467589, 33576794, 33576163, 10612833) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MYO7A: PM3:Very Strong, PM2, PM5, PP1, PP3 -

Usher syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2019	The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Janecke 1999, Pennings 2006, Pennings 2004, Roux 2006). Eleven of these probands were homozygous or compound heterozygous. It has also segregated in at least one affected sibling as observed by testing in our laboratory, and it has been reported in ClinVar (Variation ID 43218). This variant has been identified in 0.01% (12/80298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP1_Supporting, PP4. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

MYO7A-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 05, 2018	The MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome type 1 including five homozygotes, 18 compound heterozygotes, two heterozygotes, and in one individual in a double heterozygous state with a variant in the USH2A gene (Janecke et al. 1999; Bharadwaj et al. 2000; Pennings et al. 2004; Gerber et al. 2006; Pennings et al. 2006; Roux et al. 2006; Jaijo et al. 2007; Jacobsen et al. 2008; Jaijo et al. 2010; Bonnet et al. 2011; Le Quesne Stabej et al. 2012). While this variant has not been reported in conjunction with nonsyndromic hearing loss, disease risk cannot be ruled out. The variant was not found in at least 1075 healthy controls (Janecke et al. 1999; Roux et al. 2006; Jaijo et al. 2010; Bonnet et al. 2011) and is reported at a frequency of 0.000723 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the combined evidence, the p.Arg1240Gln variant is classified as pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 05, 2024	The MYO7A c.3719G>A variant is predicted to result in the amino acid substitution p.Arg1240Gln. This variant has been reported to be causative for autosomal recessive Usher syndrome (Roux et al. 2006. PubMed ID: 16679490; Bharadwaj et al. 2000. PubMed ID: 10930322; Bonnet et al. 2011. PubMed ID: 21569298; supplementary data, Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Usher syndrome type 1

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 24, 2024	- -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jan 03, 2017

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Usher syndrome type 1B

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

H;H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.95

MVP

0.97

MPC

0.50

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over