rs111033181

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PP1PP4PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The c.401T>A (p.Ile134Asn) is a missense variant in MYO7A predicted to cause a substitution of isoleucine to asparagine at amino acid 134. The filtering allele frequency (the lower threshold of the 95% CI of 60/1179894) of this variant is 0.004019% in the European (non-Finnish) population which meets the threshold (≤0.00007, 0.007%) defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction tool produced a score of 0.938, which is above the threshold necessary to apply PP3 (PP3). This variant has been detected in 7 probands with Usher syndrome. For 2 of those probands, pathogenic variants (c.19-1G>A and p.Gly214Arg) were observed in trans, and in the other 5 probands, a pathogenic variant was observed with unknown phase (4.5 points, PM3_Very Strong, PMIDs: 25468891, 26969326, 33089500, 37510321, Partners LMM Internal Data ClinVar SCV000059786.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM Internal Data ClinVar SCV000059786.6). At least one patient with this variant displayed features of sensorineural hearing loss and retinitis pigmentosa, which are consistent for Usher syndrome, a condition highly specific for MYO7A (PP4, Partners LMM Internal Data ClinVar SCV000059786.6). In summary, this variant meets 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 Expert Panel (PM3_Very Strong, PM2_Supporting, PP1, PP3, PP4). (ClinGen Hearing Loss VCEP specifications version 2; 9/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278663/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

16

2

1

Clinical Significance

Pathogenic reviewed by expert panel P:6U:1

Conservation

PhyloP100: 8.00

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:

MYO7A (HGNC:):

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is 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/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.401T>A	p.Ile134Asn	missense_variant	5/49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.401T>A	p.Ile134Asn	missense_variant	5/49	1	NM_000260.4	ENSP00000386331.3		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.401T>A	p.Ile134Asn	missense_variant	5/49	1		ENSP00000392185.2		Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.368T>A	p.Ile123Asn	missense_variant	6/50	1		ENSP00000386635.2		Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152190

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000281

AC:

7

AN:

249012

Hom.:

0

AF XY:

0.0000296

AC XY:

4

AN XY:

135134

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:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

62

AN:

1461634

Hom.:

0

Cov.:

31

AF XY:

0.0000385

AC XY:

28

AN XY:

727086

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:

0.0000375

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152190

Hom.:

0

Cov.:

33

AF XY:

0.00

AC XY:

0

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.0000283

Hom.:

0

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 134 of the MYO7A protein (p.Ile134Asn). This variant is present in population databases (rs111033181, gnomAD 0.006%). This missense change has been observed in individuals with Usher syndrome (PMID: 25468891, 26969326; Invitae). ClinVar contains an entry for this variant (Variation ID: 43230). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	Observed in multiple unrelated patients with Usher syndrome referred for genetic testing at GeneDx and in published literature (Sloan-Heggen et al., 2016; Wafa et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10930322, 10094549, 26969326, 33089500, 26582918) -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 23, 2018

- -

Usher syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 18, 2024

The c.401T>A (p.Ile134Asn) is a missense variant in MYO7A predicted to cause a substitution of isoleucine to asparagine at amino acid 134. The filtering allele frequency (the lower threshold of the 95% CI of 60/1179894) of this variant is 0.004019% in the European (non-Finnish) population which meets the threshold (≤0.00007, 0.007%) defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction tool produced a score of 0.938, which is above the threshold necessary to apply PP3 (PP3). This variant has been detected in 7 probands with Usher syndrome. For 2 of those probands, pathogenic variants (c.19-1G>A and p.Gly214Arg) were observed in trans, and in the other 5 probands, a pathogenic variant was observed with unknown phase (4.5 points, PM3_Very Strong, PMIDs: 25468891, 26969326, 33089500, 37510321, Partners LMM Internal Data ClinVar SCV000059786.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM Internal Data ClinVar SCV000059786.6). At least one patient with this variant displayed features of sensorineural hearing loss and retinitis pigmentosa, which are consistent for Usher syndrome, a condition highly specific for MYO7A (PP4, Partners LMM Internal Data ClinVar SCV000059786.6). In summary, this variant meets 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 Expert Panel (PM3_Very Strong, PM2_Supporting, PP1, PP3, PP4). (ClinGen Hearing Loss VCEP specifications version 2; 9/18/2024). -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 25, 2011

The Ile134Asn variant in MYO7A has been reported in one proband with Usher syndr ome Type I and was absent in 172 control chromosomes (Bharadwaj 2000). We have a lso observed this variant in another patient with Usher syndrome with a pathogen ic variant on the other allele. In addition, this residue is highly conserved ac ross species and computational analyses (biochemical amino acid properties, homo logy, PolyPhen2, SIFT) suggest that the variant may impact the protein. In summa ry, this data suggests this variant is likely pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 21, 2019

- -

MYO7A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 01, 2019

The MYO7A c.401T>A (p.Ile134Asn) variant is a missense variant which has been reported in two studies in which it has been identified in a compound heterozygous state in two patients with Usher syndrome (Bujakowska et al. 2014; Sloan-Heggen et al. 2016). The p.Ile134Asn variant is reported at a frequency of 0.000062 in the European (non-Finnish) population of the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. The p.Ile134Asn variant is highly conserved through evolution, and in silico tools predict the variant to be damaging for the protein function. Functional studies for the variant were not performed. Based on the limited evidence and application of the ACMG criteria, the p.Ile134Asn variant is classified as a variant of unknown significance for MYO7A-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.29

D

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

28

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.59

D

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.9

H;.;H;.

PrimateAI

Pathogenic

0.87

D

PROVEAN

Pathogenic

-5.8

D;.;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.94

P;.;.;.

Vest4

0.97

MutPred

0.90

Gain of disorder (P = 0.0391);Gain of disorder (P = 0.0391);Gain of disorder (P = 0.0391);.;

MVP

0.98

MPC

0.47

ClinPred

0.99

D

GERP RS

5.1

Varity_R

0.97

gMVP

0.93

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: rs111033181; hg19: chr11-76867068;