rs111033403

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4PP3PM3PM5

This summary comes from the ClinGen Evidence Repository: The c.397C>A variant in MYO7A is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 133 (p.His133Asn). The filtering allele frequency in gnomAD v4 is 0.01079% (147/1179888) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met). This variant has been reported as compound heterozygous, phase unknown, with a pathogenic variant in three individuals. One individual had a phenotype of Usher syndrome, one individual had congenital, severe to profound hearing loss, and one individual had inherited retinal disease (PM3, PP4; PMID:36011334, 26969326, 38219857). Two additional individuals with clinical features of Usher syndrome harbored the variant phase unknown with another variant of uncertain significance (PMID:37466950, SCV001218757.5). The computational predictor REVEL gives a score of 0.937, which is above the threshold necessary to apply PP3 (PP3). Another missense variant, c.397C>T p.His133Tyr, in the same codon has been classified as pathogenic for Usher syndrome by the ClinGen Hearing Loss VCEP (PM5; ClinVar Variation ID: 43228). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4, PP3, PM5. (ClinGen Hearing Loss VCEP specifications version 2; 03/12/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA177366/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:5

Conservation

PhyloP100: 7.89

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 6 ACMG points.

PM3

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

PM5

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

PP3

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

PP4

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.397C>A	p.His133Asn	missense_variant	Exon 5 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.397C>A	p.His133Asn	missense_variant	Exon 5 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.397C>A	p.His133Asn	missense_variant	Exon 5 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.364C>A	p.His122Asn	missense_variant	Exon 6 of 50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152260

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:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000482

AC:

AN:

248934

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000978

AC:

143

AN:

1461582

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000126

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74522

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000462

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1Uncertain:1

Sep 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal dominant 11 (MIM#601317), deafness autosomal recessive 2 (MIM#600060) and Usher syndrome, type 1B (MIM#276900). In addition, dominant negative is the suggested mechanism for missense variants in autosomal dominant inheritance (OMIM, PMID: 23383098). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is unestablished, missense variants causing autosomal dominant inheritance are rare and are not localised to a specific protein region (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin head motor domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(His133Tyr), p.(His133Asp) and p.(His133Gln) have been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. p.(His133Asp) also has an older VUS entry, and p.(His133Pro) has been classified as a VUS in ClinVar and pathogenic in the deafness variation database. p.(His133Tyr) and p.(His133Asp) have also been observed in individuals with a second MYO7A variant with Usher syndrome or profound hearing loss (PMID: 28944237, 35982127). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic in individuals with a second MYO7A variant with Usher syndrome or hearing loss (PMID: 37466950, 26969326, 36011334, DECIPHER). This variant has been classified as pathogenic once in ClinVar, as well as older VUS and likely benign entries. This variant has also been classified as pathogenic in the deafness variation database. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000260.3(MYO7A):c.133-2A>G) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome

Pathogenic:1

Mar 12, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.397C>A variant in MYO7A is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 133 (p.His133Asn). The filtering allele frequency in gnomAD v4 is 0.01079% (147/1179888) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met). This variant has been reported as compound heterozygous, phase unknown, with a pathogenic variant in three individuals. One individual had a phenotype of Usher syndrome, one individual had congenital, severe to profound hearing loss, and one individual had inherited retinal disease (PM3, PP4; PMID: 36011334, 26969326, 38219857). Two additional individuals with clinical features of Usher syndrome harbored the variant phase unknown with another variant of uncertain significance (PMID: 37466950, SCV001218757.5). The computational predictor REVEL gives a score of 0.937, which is above the threshold necessary to apply PP3 (PP3). Another missense variant, c.397C>T p.His133Tyr, in the same codon has been classified as pathogenic for Usher syndrome by the ClinGen Hearing Loss VCEP (PM5; ClinVar Variation ID: 43228). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4, PP3, PM5. (ClinGen Hearing Loss VCEP specifications version 2; 03/12/2025). -

not provided

Pathogenic:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 133 of the MYO7A protein (p.His133Asn). This variant is present in population databases (rs111033403, gnomAD 0.008%). This missense change has been observed in individuals with Usher syndrome (PMID: 26969326; internal data). ClinVar contains an entry for this variant (Variation ID: 164656). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.His133 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 16679490, 20052763), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Aug 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Autosomal dominant nonsyndromic hearing loss 11

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Uncertain:1

Jan 26, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1B

Uncertain:1

Dec 18, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;.;H;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.0

D;.;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

1.0

MVP

0.98

MPC

0.49

ClinPred

0.97

GERP RS

5.1

Varity_R

0.93

gMVP

0.92

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