11-77181589-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_SupportingPM3_StrongPP4PP1

This summary comes from the ClinGen Evidence Repository: The c.2904G>T variant in MYO7A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 968. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000064 (3/126898 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.563, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. At least one patient with this variant displayed Usher syndrome (PP4, PMID:33089500). This variant has been detected in at least five individuals with Usher syndrome. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and presumed to be in trans (c.631A>G (p.S211G) and c.3719G>A (p.D1240Q)) and three of those were confirmed in trans by family testing and all of whom had different variants on the other allele (c.224dup (p.D75fs), c.487G>C (p.G163R), c.1189G>A (p.A397T); 2.5 PM3 points, PMID:25472526, 26969326, 33089500; ClinVar Variation ID: 43325, 43218, 553215) (PM3_Strong). The variant has been reported to segregate with Usher syndrome in three affected family members from one family (PP1; PMID:33089500). Another missense variant, c.2904G>C (p.E968D), in the same codon has been reported in a patient with Usher syndrome (PMID:27460420). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing Loss VCEP (PM5 not met). 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: PM2_P, PP1, PP4, PM3_S (ClinGen Hearing Loss VCEP specifications version 2; 7/26/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278647/MONDO:0700087/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 6.16

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.

PM2

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

PM3

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

PP1

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.2904G>T	p.Glu968Asp	missense_variant, splice_region_variant	Exon 23 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.2904G>T	p.Glu968Asp	missense_variant, splice_region_variant	Exon 23 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.2904G>T	p.Glu968Asp	missense_variant, splice_region_variant	Exon 23 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.2871G>T	p.Glu957Asp	missense_variant, splice_region_variant	Exon 24 of 50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.447G>T	p.Glu149Asp	missense_variant, splice_region_variant	Exon 3 of 29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 link	n.744G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000810

AC:

AN:

247002

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1460532

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726474

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:

0.0000657

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000384

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000829

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Sep 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with autosomal recessive Usher syndrome (PMID: 10930322, 15660226, 24199935, 25472526, 26969326). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 968 of the MYO7A protein (p.Glu968Asp). This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon. This variant is present in population databases (rs111033233, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 43196). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Sep 22, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E968D missense variant in the MYO7A gene has been reported in association with Usher syndrome type I (Bharadwaj et al., 2000; Jacobson et al., 2009). In both reports, E968D was identified in a patient who also harbored a second missense variant. The c.2904 G>T pathogenic variant changes the last nucleotide in exon 23 of the MYO7A gene, which might affect the donor splice site and result in exons skipping. Splice prediction algorithms indicate that the E968D variant destroys the donor splice site. E968D was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret E968D to be a pathogenic variant. -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1B

Pathogenic:1

Aug 03, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2904G>T variant in MYO7A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 968. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000064 (3/126898 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.563, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. At least one patient with this variant displayed Usher syndrome (PP4, PMID: 33089500). This variant has been detected in at least five individuals with Usher syndrome. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and presumed to be in trans (c.631A>G (p.S211G) and c.3719G>A (p.D1240Q)) and three of those were confirmed in trans by family testing and all of whom had different variants on the other allele (c.224dup (p.D75fs), c.487G>C (p.G163R), c.1189G>A (p.A397T); 2.5 PM3 points, PMID: 25472526, 26969326, 33089500; ClinVar Variation ID: 43325, 43218, 553215) (PM3_Strong). The variant has been reported to segregate with Usher syndrome in three affected family members from one family (PP1; PMID:33089500). Another missense variant, c.2904G>C (p.E968D), in the same codon has been reported in a patient with Usher syndrome (PMID:27460420). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing Loss VCEP (PM5 not met). 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: PM2_P, PP1, PP4, PM3_S (ClinGen Hearing Loss VCEP specifications version 2; 7/26/2022). -

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

Pathogenic:1

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

May 15, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu968Asp variant in MYO7A has been identified at least 7 individuals with clinical features of Usher syndrome, including 1 homozygote and 5 compound hete rozygotes (Bharadwaj 2000, Ouyang 2005, Jacobson 2008, Le Quesne 2012, Bujakowsk a 2014, Zhao 2015, Sloan-Heggen 2016, Bonnet 2016, LMM unpublished data). This v ariant has been identified in 4/125720 European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033233). Al though this variant has been seen in the general population, its frequency is lo w enough to be consistent with a recessive carrier frequency. The p.Glu968Asp va riant is located in the last base of the exon, which is part of the 5? splice re gion and computational tools predict altered splicing. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon proband counts, frequency in controls, and predicte d impact on protein. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PM2, PVS1_M oderate. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.;.;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.47

T;T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.2

M;.;M;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

N;.;N;N;.;N

REVEL

Uncertain

0.56

Sift

Benign

0.22

T;.;T;T;.;T

Sift4G

Benign

0.18

T;T;T;T;.;D

Polyphen

0.21

B;.;.;.;.;.

Vest4

0.74

MutPred

0.14

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;.;

MVP

0.92

MPC

0.44

ClinPred

0.92

GERP RS

5.3

Varity_R

0.37

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: -44

DS_DL_spliceai

0.95

Position offset: 0

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