rs797044491

Positions:

chr11-77158404-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PP4PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.977T>A variant in MYO7A is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 326 (p.Leu326Gln). The highest population filtering allele frequency in gnomAD v4.1 is 0.00002995 (7/91056 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.991, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with autosomal recessive Usher syndrome. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (1.5 PM3 points, SCV000199549.4, SCV000589578.6, Laboratory for Molecular Medicine, GeneDx). One individual was homozygous for the variant (0.5 PM3 points, PMID:18181211) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000199549.4, Laboratory for Molecular Medicine). 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 VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA278720/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:2

Conservation

PhyloP100: 8.02

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 7 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/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.977T>A	p.Leu326Gln	missense_variant	9/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.977T>A	p.Leu326Gln	missense_variant	9/49	1	NM_000260.4	ENSP00000386331		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.977T>A	p.Leu326Gln	missense_variant	9/49	1		ENSP00000392185	P1	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.944T>A	p.Leu315Gln	missense_variant	10/50	1		ENSP00000386635		Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152026

Hom.:

Cov.:

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460228

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726422

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 326 of the MYO7A protein (p.Leu326Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome (PMID: 18181211). ClinVar contains an entry for this variant (Variation ID: 164664). 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. This variant disrupts the p.Leu326 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 25558175), which suggests that this may be a clinically significant amino acid residue. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2024	Observed with no second variant in an individual with hearing loss in published literature (PMID: 22135276); Not observed at significant frequency in large population cohorts (gnomAD); 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: 33269433, 33671976, 18181211, 22135276, LimSO2021[Article]) -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The observed missense c.977T>A(p.Leu326Gln) variant in MYO7A gene has been reported previously in homozygous and compound heterozygous state in multiple individuals affected with MYO7A-related disorders (Sodi A, et al., 2014; Le Quesne Stabej P, et al., 2012; Riazuddin S, et al., 2008). The p.Leu326Gln variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid change p.Leu326Gln in MYO7A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 326 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. -

Usher syndrome

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 24, 2024

The c.977T>A variant in MYO7A is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 326 (p.Leu326Gln). The highest population filtering allele frequency in gnomAD v4.1 is 0.00002995 (7/91056 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.991, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with autosomal recessive Usher syndrome. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (1.5 PM3 points, SCV000199549.4, SCV000589578.6, Laboratory for Molecular Medicine, GeneDx). One individual was homozygous for the variant (0.5 PM3 points, PMID: 18181211) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000199549.4, Laboratory for Molecular Medicine). 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 VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024) -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2013

The Leu326Gln variant in MYO7A has been reported in two individuals with clinica l features of Usher syndrome, one of whom was homozygous ( Riazuddin 2008, Le Qu esne Stabej 2012). In addition, this variant was identified in trans with a seco nd pathogenic MYO7A variant in this individual, supporting a likely pathogenic r ole. Furthermore, computational analyses (biochemical amino acid properties, con servation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact t he protein. In summary, this variant is likely to be pathogenic, though addition al studies are required to fully establish its clinical significance. -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 10, 2021

NM_000260.3(MYO7A):c.977T>A(L326Q) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. L326Q has been observed in cases with relevant disease (PMID: 22135276, 18181211, 33269433, 30303587). Functional assessments of this variant are not available in the literature. L326Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.977T>A(L326Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

MYO7A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 13, 2017

The MYO7A c.977T>A (p.Leu326Gln) missense variant has been reported in two studies in which it is found in two individuals with MYO7A-Related Disorders. The p.Leu326Gln variant was found in a homozygous state in one individual with Usher syndrome and in a heterozygous state (with a presumed unknown second allele) in one individual with atypical Usher syndrome (Riazuddin et al. 2008; Le Quesne Stabej et al. 2012). The p.Leu326Gln variant was absent from 1164 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database and is in a region of good sequence coverage, so the variant is presumed to be rare. Another variant with a different amino acid change at the same residue (p.Leu326Pro) has also been detected in an individual with type 1 Usher syndrome in a compound heterozygous state (Sodi et al. 2014). This variant has not been reported in association with autosomal dominant or autosomal recessive nonsyndromic hearing loss. Based on the evidence, the p.Leu326Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.8

D;.;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.99

MutPred

0.92

Loss of stability (P = 0.0359);Loss of stability (P = 0.0359);Loss of stability (P = 0.0359);.;

MVP

0.98

MPC

0.48

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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