11-77205599-G-A

Position:

chr11-77205599-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPM5PP1PP4PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Arg1873Gln variant in the MYO7A gene is 0.008% (2/24854) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and 2 probands with Usher syndrome. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, for 1 proband a pathogenic or suspected-pathogenic was suspected in trans, and for 1 of the probands, a rare variant of uncertain significance was observed in trans (PM3_Strong; PMID:23208854, 28000701, 29196752, Partners LMM internal data SCV000059849.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM internal data SCV000059849.6). A different pathogenic missense variant (p.Arg1873Trp) has been previously identified at this codon of MYO7A which may indicate that this residue is critical to the function of the protein (PM5; p.Arg1873Trp ClinVar Variation ID 43291). The REVEL computational prediction analysis tool produced a score of 0.936, which is above the threshold necessary to apply PP3. At least one of the above patients with the variant in this gene displayed features of Usher syndrome (PP4; Partners LMM internal data SCV000059849.6). 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 Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PM5, PP1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA278687/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

13

5

1

Clinical Significance

Pathogenic reviewed by expert panel P:7U:2

Conservation

PhyloP100: 9.56

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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.

PM5

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.5618G>A	p.Arg1873Gln	missense_variant	40/49	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.5618G>A	p.Arg1873Gln	missense_variant	40/49	1	NM_000260.4	ENSP00000386331.3		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.5504G>A	p.Arg1835Gln	missense_variant	40/49	1		ENSP00000392185.2		Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.5471G>A	p.Arg1824Gln	missense_variant	41/50	1		ENSP00000386635.2		Q13402-8
MYO7A	ENST00000458169.2 linkuse as main transcript	c.3044G>A	p.Arg1015Gln	missense_variant	20/29	1		ENSP00000417017.2		H7C4D8
MYO7A	ENST00000670577.1 linkuse as main transcript	n.*216G>A		non_coding_transcript_exon_variant	23/32			ENSP00000499323.1		A0A590UJ94
MYO7A	ENST00000670577.1 linkuse as main transcript	n.*216G>A		3_prime_UTR_variant	23/32			ENSP00000499323.1		A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

8

AN:

152178

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000283

AC:

7

AN:

247780

Hom.:

0

AF XY:

0.0000297

AC XY:

4

AN XY:

134666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000936

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000582

AC:

85

AN:

1461236

Hom.:

0

Cov.:

32

AF XY:

0.0000550

AC XY:

40

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

8

AN:

152178

Hom.:

0

Cov.:

32

AF XY:

0.0000538

AC XY:

4

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000653

Hom.:

0

Bravo

AF:

0.0000529

ExAC

AF:

0.0000165

AC:

2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:2

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27068579, 16963483, 23208854) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1873 of the MYO7A protein (p.Arg1873Gln). 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 nonsyndromic deafness (PMID: 23208854, 27068579). This variant is also known as p.Arg1835Gln. ClinVar contains an entry for this variant (Variation ID: 43292). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. This variant disrupts the p.Arg1873 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16679490, 28472130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Feb 15, 2018

- -

Usher syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Nov 26, 2019

The allele frequency of the p.Arg1873Gln variant in the MYO7A gene is 0.008% (2/24854) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and 2 probands with Usher syndrome. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, for 1 proband a pathogenic or suspected-pathogenic was suspected in trans, and for 1 of the probands, a rare variant of uncertain significance was observed in trans (PM3_Strong; PMID:23208854, 28000701, 29196752, Partners LMM internal data SCV000059849.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM internal data SCV000059849.6). A different pathogenic missense variant (p.Arg1873Trp) has been previously identified at this codon of MYO7A which may indicate that this residue is critical to the function of the protein (PM5; p.Arg1873Trp ClinVar Variation ID 43291). The REVEL computational prediction analysis tool produced a score of 0.936, which is above the threshold necessary to apply PP3. At least one of the above patients with the variant in this gene displayed features of Usher syndrome (PP4; Partners LMM internal data SCV000059849.6). 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 Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PM5, PP1, PP3, PP4. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 25, 2011

The Arg1873Gln variant in MYO7A has been identified in one proband with Usher ty pe I (Cremers 2007). In addition, this residue is highly conserved across evolut ionary distant species and computational analyses (PolyPhen2, SIFT) suggest that the variant may impact the protein. Furthermore, a different variant at the sam e position, Arg1873Trp, has been reported in five probands with Usher syndrome T ype 1 and is classified as pathogenic. In summary, the Arg1873Gln variant is lik ely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

D

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.41

D

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.1

M;.;.;.

PrimateAI

Uncertain

0.75

T

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.99

D;.;.;.

Vest4

0.92

MVP

0.98

MPC

0.33

ClinPred

0.99

D

GERP RS

4.7

Varity_R

0.95

gMVP

0.77

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: rs397516322; hg19: chr11-76916644;