chr11-77159450-G-A

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 was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID:16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). 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. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2. 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

4
8
7

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]

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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
MYO7ANM_000260.4 linkc.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 Appris UniProt
MYO7AENST00000409709.9 linkc.1007G>A p.Arg336His missense_variant Exon 10 of 49 1 NM_000260.4 ENSP00000386331.3 Q13402-1
MYO7AENST00000458637.6 linkc.1007G>A p.Arg336His missense_variant Exon 10 of 49 1 ENSP00000392185.2 Q13402-2
MYO7AENST00000409619.6 linkc.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.:
0
Cov.:
29
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.:
1
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.:
4
Cov.:
35
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.:
0
Cov.:
29
AF XY:
0.00151
AC XY:
92
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.:
1
Bravo
AF:
0.00125
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00493
AC:
19
ESP6500AA
AF:
0.000508
AC:
2
ESP6500EA
AF:
0.00193
AC:
16
ExAC
AF:
0.00115
AC:
139
Asia WGS
AF:
0.000289
AC:
1
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
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

- -

Jan 18, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
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

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. -

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

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 Benign:1
Nov 02, 2020
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 was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID: 16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). 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. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2. -

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
T
BayesDel_noAF
Pathogenic
0.28
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.64
D;T;.;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.099
T;T;T;T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
0.97
L;.;L;.
PrimateAI
Uncertain
0.66
T
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
T
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.

Other links and lift over

dbSNP: rs45629132; hg19: chr11-76870496; COSMIC: COSV68684980; API