rs199818783

Positions:

chr11-77160214-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000260.4(MYO7A):c.1132C>T(p.Arg378Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,581,022 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R378R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 1.28

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	11/49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	11/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	11/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	12/50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000302

AC:

AN:

195244

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

105158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000403

Gnomad FIN exome

AF:

0.000646

Gnomad NFE exome

AF:

0.000462

Gnomad OTH exome

AF:

0.000592

GnomAD4 exome

AF:

0.000283

AC:

405

AN:

1428842

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

182

AN XY:

707576

show subpopulations

Gnomad4 AFR exome

AF:

0.0000920

Gnomad4 AMR exome

AF:

0.000198

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.000830

Gnomad4 NFE exome

AF:

0.000295

Gnomad4 OTH exome

AF:

0.000439

GnomAD4 genome

AF:

0.000204

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000438

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.000301

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2022	Identified in patients with symptoms of Usher syndrome in published literature, although information about additional variants and clinical information is limited or unavailable (Cremers et al., 2007; Wang et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28838317, 16963483) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the MYO7A protein (p.Arg378Cys). This variant is present in population databases (rs199818783, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43135). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinal dystrophy

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 02, 2018	- -

Autosomal dominant nonsyndromic hearing loss 11

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 24, 2019	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2013

The Arg378Cys variant in MYO7A has been previously identified by our laboratory in one individual with Usher syndrome; however, the variant was heterozygous in this individual and a second MYO7A variant was not detected (LMM unpublished da ta). It has also been identified in 0.04% (3/8378) of European American chromos omes by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS; db SNP rs199818783). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational a nalyses (biochemical, amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein . In summary, additional information is needed to determine the clinical signifi cance of this variant. -

Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Feb 07, 2017

- -

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 12, 2020

- -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

MYO7A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2024

The MYO7A c.1132C>T variant is predicted to result in the amino acid substitution p.Arg378Cys. This variant was reported in a study of patients with Usher syndrome (Supplementary Table 1, Cremers et al. 2006. PubMed ID: 16963483). However, clinical or functional data was not provided in this study. This variant is reported in 0.083% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant many benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.72

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.2

M;.;M;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.7

D;.;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.88

MVP

0.93

MPC

0.54

ClinPred

0.28

GERP RS

4.1

Varity_R

0.82

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.

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