rs111033486

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PM2_SupportingPM3PP3PP4

This summary comes from the ClinGen Evidence Repository: The c.631A>G variant in MYO7A is a missense variant predicted to cause substitution of serine by glycine at amino acid 211 (p.Ser211Gly). The highest population minor allele frequency in gnomAD v4.1.0 is 0.005% (62/1179900 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 7 individuals with clinical features or a diagnosis of Usher syndrome. Of those individuals, 2 were homozygous, and 5 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (4.5 PM3 points, PMID:25472526 and 37466950, Laboratory for Molecular Medicine internal data, SCV000059882.6). At least one patient with this variant displayed congenital profound sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction, which is highly specific for Usher syndrome type 1 (PP4). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PM3_VeryStrong, PP4. ClinGen Hearing Loss VCEP specifications version 2.0.0; 04.17.24. LINK:https://erepo.genome.network/evrepo/ui/classification/CA278707/MONDO:0019501/005

Frequency

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

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:7U:1

Conservation

PhyloP100: 5.03

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 Pathogenic. Variant got 5 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.

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.631A>G	p.Ser211Gly	missense_variant	Exon 7 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.631A>G	p.Ser211Gly	missense_variant	Exon 7 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.631A>G	p.Ser211Gly	missense_variant	Exon 7 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.598A>G	p.Ser200Gly	missense_variant	Exon 8 of 50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249174

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135190

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:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727124

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:

0.0000495

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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:

0.000141

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome

Pathogenic:2

Mar 13, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser211Gly variant in MYO7A has been reported in 3 individuals with clinical features of Usher syndrome (Zhao 2015; LMM internal data). It has also been identified in 0.005% (7/128370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs111033486). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP3, PP4 -

May 01, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.631A>G variant in MYO7A is a missense variant predicted to cause substitution of serine by glycine at amino acid 211 (p.Ser211Gly). The highest population minor allele frequency in gnomAD v4.1.0 is 0.005% (62/1179900 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 7 individuals with clinical features or a diagnosis of Usher syndrome. Of those individuals, 2 were homozygous, and 5 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (4.5 PM3 points, PMID:25472526 and 37466950, Laboratory for Molecular Medicine internal data, SCV000059882.6). At least one patient with this variant displayed congenital profound sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction, which is highly specific for Usher syndrome type 1 (PP4). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PM3_VeryStrong, PP4. ClinGen Hearing Loss VCEP specifications version 2.0.0; 04.17.24. -

not provided

Pathogenic:2

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 211 of the MYO7A protein (p.Ser211Gly). This variant is present in population databases (rs111033486, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of autosomal recessive Usher syndrome (PMID: 25472526; Invitae). ClinVar contains an entry for this variant (Variation ID: 43325). 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%. For these reasons, this variant has been classified as Pathogenic. -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO7A: PM3:Strong, PP4:Moderate, PM2:Supporting, PP3 -

Usher syndrome type 1B

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:1

Apr 08, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

Jan 02, 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

0.94

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;.;H;.

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.4

D;.;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.99

MutPred

0.94

Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);.;

MVP

0.94

MPC

0.45

ClinPred

1.0

GERP RS

5.2

Varity_R

0.96

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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