rs111033437

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP1_StrongPP3PM2_SupportingPS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2558G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 853. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been reported in 3 probands/families with hearing loss (PS4_Supporting; PMIDs: 26969326, 32097363, ClinVar SCV: SCV000059742.6, LMM). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID:32097363). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PS4_P, PM2_P, PP3 (Hearing Loss VCEP specifications version 2; 10/31/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132255/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

MYO7A
ENST00000409709.9 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:3

Conservation

PhyloP100: 9.96

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 Likely_pathogenic. Variant got 7 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.2558G>A	p.Arg853His	missense_variant	21/49	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.2558G>A	p.Arg853His	missense_variant	21/49	1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000725

AC:

AN:

1379648

Hom.:

Cov.:

AF XY:

0.00000589

AC XY:

AN XY:

679390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000282

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000745

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000305

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 853 of the MYO7A protein (p.Arg853His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 32097363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43186). 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 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as likely pathogenic by the ClinGen Hearing Loss Expert Panel (PMID: 30311386); This variant is associated with the following publications: (PMID: 33724713, 26969326, 35453549, 23804846, 32097363, 34387732, 30311386) -

Autosomal dominant nonsyndromic hearing loss 11

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Apr 24, 2018	The variant was identified using linkage analysis from a pedigree showing hearing loss for 5-generations. The locus between rs1462224 and rs591804 showed HLOD score >3.0. Variants of the two deafness genes (CABP2 and LRTOMT) on the locus were not cosegregated with hearing loss. MYO7A was mapped on the adjacent region, where the LOD score was >2.0. -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Oct 31, 2022

The c.2558G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 853. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been reported in 3 probands/families with hearing loss (PS4_Supporting; PMIDs: 26969326, 32097363, ClinVar SCV: SCV000059742.6, LMM). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID: 32097363). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PS4_P, PM2_P, PP3 (Hearing Loss VCEP specifications version 2; 10/31/2022). -

MYO7A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

The MYO7A c.2558G>A variant is predicted to result in the amino acid substitution p.Arg853His. This variant segregated with autosomal dominant hearing loss across three generations of a single family of 11 affected and 11 unaffected individuals. Hearing loss was mild to moderate with a flat to sloping audiogram with onset between one and 33 years of age (Yamamoto et al 2020. PubMed ID: 32097363). This variant has also been reported in multiple simplex patients with hearing loss, although conclusive evidence of pathogenicity was not presented (Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326; Table S3, Shearer et al. 2013. PubMed ID: 23804846; Li et al. 2021. PubMed ID: 33724713). A different substitution (Cys) at the same amino acid position has been reported as pathogenic for autosomal dominant nonsyndromic hearing loss (Bolz et al. 2004. PubMed ID: 15300860). A ClinGen Hearing Loss expert panel classifies this variant as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/43186/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2013

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg853His v ariant in MYO7A has been reported in a German family with autosomal dominant pro gressive hearing loss where it was shown to segregate with hearing loss in 4 aff ected family members (Bolz 2004). An impact to protein function was proposed by the authors based upon an in vitro assay. The variant has also been reported in another individual with hearing loss; however phenotypic data for this individu al (including a likely inheritance pattern) was not provided (Shearer 2013). Dat a from large population studies is insufficient, and computational analyses (bio chemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary , additional information is needed to fully assess the clinical significance of the Arg853His variant. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;T;.;.;.;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.3

M;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.7

D;.;D;D;.;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.012

D;.;D;D;.;D

Sift4G

Uncertain

0.0060

D;D;D;D;.;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.80

MutPred

0.52

Loss of methylation at R853 (P = 0.0909);Loss of methylation at R853 (P = 0.0909);Loss of methylation at R853 (P = 0.0909);.;.;.;

MVP

0.98

MPC

0.52

ClinPred

1.0

GERP RS

5.6

Varity_R

0.41

gMVP

0.63

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

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