rs397516292

Positions:

chr11-77174822-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000260.4(MYO7A):c.2002C>T(p.Arg668Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R668H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 1.89

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 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-77174823-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.2002C>T	p.Arg668Cys	missense_variant	17/49	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.2002C>T	p.Arg668Cys	missense_variant	17/49	1	NM_000260.4	ENSP00000386331		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.2002C>T	p.Arg668Cys	missense_variant	17/49	1		ENSP00000392185	P1	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.1969C>T	p.Arg657Cys	missense_variant	18/50	1		ENSP00000386635		Q13402-8
MYO7A	ENST00000409893.6 linkuse as main transcript	c.67C>T	p.Arg23Cys	missense_variant	1/11	5		ENSP00000386689

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000810

AC:

AN:

246942

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134442

show subpopulations

Gnomad AFR exome

AF:

0.0000656

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:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1460964

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000432

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue p.(R668H) has been reported as pathogenic in the published literature in association with nonsyndromic hearing loss (Sang et al., 2013); This variant is associated with the following publications: (PMID: 20146813, 16283880, 26969326) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 668 of the MYO7A protein (p.Arg668Cys). This variant is present in population databases (rs397516292, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 26969326; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43168). 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.Arg668 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26969326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg668Cys v ariant in MYO7A has not been reported in the literature nor previously identifie d by our laboratory. Computational analyses (biochemical amino acid properties, conservation, SIFT, PolyPhen2) suggest that the Arg668Cys variant may impact the protein, though this information is not predictive enough to determine pathogen icity. If the Arg668Cys variant is found to be in trans (on separate copies of t he gene) with the Tyr333X variant, then the presence of the Arg668Cys variant in combination with a pathogenic variant in a patient with hearing loss increases the likelihood that the Arg668Cys variant is pathogenic. In summary, the clinica l significance of this variant cannot be determined with certainty; however base d upon the arguments described above, and if the Arg668Cys variant is shown to b e in trans, we would lean towards a more likely pathogenic role for this variant . -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 03, 2021

NM_000260.3(MYO7A):c.2002C>T(R668C) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R668C has been observed in cases with relevant disease (PMID: 26969326, 16283880, 20146813). Functional assessments of this variant are not available in the literature. R668C has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.2002C>T(R668C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;T;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.2

M;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.8

D;.;D;D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.95

MVP

0.91

MPC

0.54

ClinPred

1.0

GERP RS

5.2

Varity_R

0.89

gMVP

0.83

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