11-77206120-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000260.4(MYO7A):c.5660C>T(p.Pro1887Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1887T) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.56

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
Usher syndrome type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant nonsyndromic hearing loss 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000260.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-77206119-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3601491.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 11-77206120-C-T is Pathogenic according to our data. Variant chr11-77206120-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.5660C>T	p.Pro1887Leu	missense_variant	Exon 41 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYO7A	ENST00000409709.9 link	c.5660C>T	p.Pro1887Leu	missense_variant	Exon 41 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6 link	c.5546C>T	p.Pro1849Leu	missense_variant	Exon 41 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6 link	c.5513C>T	p.Pro1838Leu	missense_variant	Exon 42 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2 link	c.3086C>T	p.Pro1029Leu	missense_variant	Exon 21 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1 link	n.*258C>T		non_coding_transcript_exon_variant	Exon 24 of 32			ENSP00000499323.1
MYO7A	ENST00000670577.1 link	n.*258C>T		3_prime_UTR_variant	Exon 24 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247110

AF XY:

0.00000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460744

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

85980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111534

Other (OTH)

AF:

0.0000166

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000212

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 31, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Segregates with nonsyndromic hearing loss in multiple affected homozygous individuals from a single family in published literature (Ben-Salem et al., 2014); 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: 26968074, 24194196, 10930322, 25468891, 33111992, 33671976, 30303587) -

Feb 27, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1887 of the MYO7A protein (p.Pro1887Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive MYO7A-related conditions (PMID: 10930322, 24194196, 25468891). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43295). 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. -

Usher syndrome type 1

Pathogenic:2

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The MYO7A c.5660C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PP1-S, PM3-S. Based on this evidence we have classified this variant as Pathogenic. -

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043295). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:24194196). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Pathogenic:1

Sep 01, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hearing loss, autosomal recessive

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Rare genetic deafness

Pathogenic:1

Aug 15, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-9.5

D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.99

MutPred

0.73

Loss of catalytic residue at P1886 (P = 0.0151);.;.;.;

MVP

0.97

MPC

0.47

ClinPred

1.0

GERP RS

4.5

Varity_R

0.94

gMVP

0.86

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over