chr11-77184688-G-T

Position:

chr11-77184688-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000409709.9(MYO7A):c.3476G>T(p.Gly1159Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,599,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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. G1159S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

MYO7A
ENST00000409709.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 9.59

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 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000409709.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-77184687-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 11-77184688-G-T is Pathogenic according to our data. Variant chr11-77184688-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77184688-G-T is described in Lovd as [Likely_pathogenic]. Variant chr11-77184688-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.3476G>T	p.Gly1159Val	missense_variant	27/49	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.3476G>T	p.Gly1159Val	missense_variant	27/49	1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

224146

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

121436

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:

0.000493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000426

AC:

616

AN:

1447080

Hom.:

Cov.:

AF XY:

0.000422

AC XY:

303

AN XY:

718382

show subpopulations

Gnomad4 AFR exome

AF:

0.0000904

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:

0.000544

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.000210

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000400

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MYO7A: PM3:Strong, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1159 of the MYO7A protein (p.Gly1159Val). This variant is present in population databases (rs199897298, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness or Usher syndrome (PMID: 21436283, 23208854, 26969326, 27068579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1019G>T (p.Gly340Val). ClinVar contains an entry for this variant (Variation ID: 43206). 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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2024	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: 26486028, 31589614, 31964843, 26969326, 23208854, 27068579, 21436283, 30245029, 27160483, 32795431, 36515421, 35885997) -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal dominant 11 (MIM#601317), deafness autosomal recessive 2 (MIM#600060) and Usher syndrome, type 1B (MIM#276900). In addition, dominant negative is the suggested mechanism for missense variants in autosomal dominant inheritance (OMIM, PMID: 23383098). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is unestablished, missense variants causing autosomal dominant inheritance are rare and are not localised to a specific protein region (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (58 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MyTH4 domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. This alternative change (p.(Gly1159Ser)) has been reported as a VUS (ClinVar) and as pathogenic (deafnessvariationdatabase.org), and has been observed in an individual with hearing loss (PMID: 25587757). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and observed in multiple compound heterozygous individuals with deafness, Usher syndrome and/or retinitis pigmentosa (ClinVar, deafnessvariationdatabase.org, PMID: 32795431, PMID: 31152317). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

Retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 04, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -

Hearing loss

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Aug 15, 2019

- -

Usher syndrome type 1B

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

MYO7A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 01, 2024

Variant summary: MYO7A c.3476G>T (p.Gly1159Val) results in a non-conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 224146 control chromosomes, allowing no conclusion about variant significance. c.3476G>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal recessive non-syndromic hearing loss (e.g. Roux_2011, Schrauwen_2013, Sloan-Heggen_2016, Sommen_2016, Zazo-Seco_2017, van Beeck Calkoen_2019) and in at least one compound heterozygous individual with retinitis pigmentosa (Georgiou_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32795431, 21436283, 23208854, 26969326, 27068579, 28000701, 31152317). ClinVar contains an entry for this variant (Variation ID: 43206). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 17, 2021

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 13, 2016

The p.Gly1159Val variant in MYO7A has been reported in 9 individuals with hearin g loss (Roux 2011, Schrauwen 2013, LMM data). Four of these individuals were co mpound heterozygous with a second pathogenic or likely pathogenic MYO7A variant, with no indication of retinitis pigmentosa associated with Usher syndrome. Anot her with retinitis pigmentosa had a second variant of uncertain significance in MYO7A. This individual also reportedly has LCHAD, which may explain the retiniti s pigmentosa. This variant has been identified in 12/30732 (0.04%) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199897298); however, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, althoug h additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. However, it cannot be determined whether this variant causes type 1 Usher syndrome, atyp ical Usher syndrome, or nonsyndromic hearing loss without additional information . -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 01, 2024

Variant summary: PALB2 c.3476G>T (p.Trp1159Leu) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3476G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homologous recombination or in a PARP inhibitor sensitivity assay (e.g., Boonen_2019). The following publication was ascertained in the context of this evaluation (PMID: 31757951). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;T;.;.;.;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.5

D;.;D;D;.;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;D;D;.;D

Sift4G

Uncertain

0.0020

D;D;D;D;.;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.98

MVP

0.99

MPC

0.52

ClinPred

0.94

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.71

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.

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