chr11-77159450-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_SupportingBP2

This summary comes from the ClinGen Evidence Repository: The c.1007G>A (p.Arg336His) variant in MYO7A is a missense variant predicted to cause a substitution of arginine by histidine at amino acid 336. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00286 (2854/996858) in the non-Finnish European population, including 4 homozygous individuals, at least two of whom were beyond the average age of onset for MYO7A-related Usher syndrome. This frequency is higher than would be expected for an autosomal recessive condition based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been reported in individuals with nonsyndromic, mild-moderate hearing loss in whom a second variant was not detected (PMID:23804846) as well as an individual with Usher syndrome but lacking a second variant (PMID:16470552). A patient with Usher syndrome was homozygous for both p.Arg336His and a likely pathogenic/pathogenic variant (BP2; PMID:33363762, ClinVar IDs: 551533). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign for both Usher syndrome and nonsyndromic hearing loss. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132194/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0023 ( 4 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:5B:10

Conservation

PhyloP100: 7.72

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_benign. Variant got -2 ACMG points.

BP2

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.1007G>A	p.Arg336His	missense_variant	Exon 10 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 link	c.1007G>A	p.Arg336His	missense_variant	Exon 10 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.1007G>A	p.Arg336His	missense_variant	Exon 10 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.974G>A	p.Arg325His	missense_variant	Exon 11 of 50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

210

AN:

129680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000931

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000904

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000245

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00261

Gnomad OTH

AF:

0.000559

GnomAD3 exomes

AF:

0.00116

AC:

288

AN:

247514

Hom.:

AF XY:

0.00105

AC XY:

141

AN XY:

134430

show subpopulations

Gnomad AFR exome

AF:

0.000713

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00221

Gnomad OTH exome

AF:

0.000830

GnomAD4 exome

AF:

0.00234

AC:

2822

AN:

1204636

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1372

AN XY:

597724

show subpopulations

Gnomad4 AFR exome

AF:

0.000556

Gnomad4 AMR exome

AF:

0.000578

Gnomad4 ASJ exome

AF:

0.000171

Gnomad4 EAS exome

AF:

0.0000423

Gnomad4 SAS exome

AF:

0.0000479

Gnomad4 FIN exome

AF:

0.000407

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00162

AC:

210

AN:

129732

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

AN XY:

61010

show subpopulations

Gnomad4 AFR

AF:

0.000930

Gnomad4 AMR

AF:

0.000902

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000246

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000161

Gnomad4 NFE

AF:

0.00261

Gnomad4 OTH

AF:

0.000555

Alfa

AF:

0.00187

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000508

AC:

ESP6500EA

AF:

0.00193

AC:

ExAC

AF:

0.00115

AC:

139

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00175

EpiControl

AF:

0.00166

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30311386, 30245029, 15221449, 16470552, 25262649) -

Autosomal dominant nonsyndromic hearing loss 11

Uncertain:1Benign:1

Sep 24, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome type 1

Uncertain:1Benign:1

Nov 04, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000260.3(MYO7A):c.1007G>A(R336H) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R336H has been observed in cases with relevant disease (PMID: 23804846, 16470552, 33363762). Functional assessments of this variant are not available in the literature. R336H has been observed in population frequency databases (gnomAD: NFE 0.22%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.1007G>A(R336H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified

Benign:2

Aug 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg336His in exon 10 of MYO7A: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (125/66438) of European chrom osomes including 1 homozygous individual by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs45629132). This variant has been re ported in the literature; however, there is no evidence to support pathogenicity . It was identified in a family with autosomal dominant hearing loss but found n ot to segregate with disease and therefore assumed to be benign (Luijendijk 2004 ). It was also identified in the heterozygous state in a proband with Usher synd rome without a second variant (Jaijo 2006). -

Mar 02, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meniere disease

Uncertain:1

Dec 14, 2020

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome

Benign:1

Nov 20, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.1007G>A (p.Arg336His) variant in MYO7A is a missense variant predicted to cause a substitution of arginine by histidine at amino acid 336. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00286 (2854/996858) in the non-Finnish European population, including 4 homozygous individuals, at least two of whom were beyond the average age of onset for MYO7A-related Usher syndrome. This frequency is higher than would be expected for an autosomal recessive condition based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been reported in individuals with nonsyndromic, mild-moderate hearing loss in whom a second variant was not detected (PMID: 23804846) as well as an individual with Usher syndrome but lacking a second variant (PMID: 16470552). A patient with Usher syndrome was homozygous for both p.Arg336His and a likely pathogenic/pathogenic variant (BP2; PMID: 33363762, ClinVar IDs: 551533). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign for both Usher syndrome and nonsyndromic hearing loss. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). -

Usher syndrome type 1B

Benign:1

Apr 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

MYO7A-related disorder

Benign:1

Nov 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;T;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.099

T;T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

0.97

L;.;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.3

N;.;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.069

T;.;T;T

Sift4G

Benign

0.070

T;T;T;T

Polyphen

0.99

D;.;.;.

Vest4

0.83

MVP

0.95

MPC

0.11

ClinPred

0.027

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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