rs797044511

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. PM2_SupportingPP3PP1PP4PM3

This summary comes from the ClinGen Evidence Repository: The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). 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 Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA278736/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MYO7A
NM_000260.4 missense

Scores

17

1

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:2

Conservation

PhyloP100: 9.32

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.

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.

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.1208A>G	p.Tyr403Cys	missense_variant	Exon 12 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 link	c.1208A>G	p.Tyr403Cys	missense_variant	Exon 12 of 49	1	NM_000260.4	ENSP00000386331.3		Q13402-1
MYO7A	ENST00000458637.6 link	c.1208A>G	p.Tyr403Cys	missense_variant	Exon 12 of 49	1		ENSP00000392185.2		Q13402-2
MYO7A	ENST00000409619.6 link	c.1175A>G	p.Tyr392Cys	missense_variant	Exon 13 of 50	1		ENSP00000386635.2		Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

1

AN:

152074

Hom.:

0

Cov.:

32

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

Cov.:

31

GnomAD4 genome

AF:

0.00000658

AC:

1

AN:

152074

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the MYO7A protein (p.Tyr403Cys). This variant is present in population databases (rs797044511, gnomAD 0.001%). This missense change has been observed in individual(s) with Usher syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 178667). 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 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 09, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome

Pathogenic:1

Dec 21, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). 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 Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) -

Rare genetic deafness

Pathogenic:1

Jun 12, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Tyr403Cys in MYO7A has been identified in two siblings with clinical feature s of Usher syndrome by our laboratory. Both siblings carried a second MYO7A vari ant on the other MYO7A allele. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest tha t the Tyr403Cys variant may impact the protein. In summary, this variant is like ly to be pathogenic, though additional studies are required to fully establish i ts clinical significance. -

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

Uncertain:1

Feb 20, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.48

D

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.81

D

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.6

H;.;H;.

PrimateAI

Pathogenic

0.89

D

PROVEAN

Pathogenic

-8.7

D;.;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.99

MutPred

0.79

Loss of MoRF binding (P = 0.1165);Loss of MoRF binding (P = 0.1165);Loss of MoRF binding (P = 0.1165);.;

MVP

0.97

MPC

0.52

ClinPred

1.0

D

GERP RS

5.2

Varity_R

0.94

gMVP

0.92

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.

Other links and lift over

dbSNP: rs797044511; hg19: chr11-76872026;