rs797044511

Positions:

• chr11-77160980-A-G
• chr11-77160980-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3 PP3 PP1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). 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 Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA278736/MONDO:0019501/005

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MYO7A ENST00000409709.9 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• 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	c.1208A>G	p.Tyr403Cys	missense_variant	12/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1208A>G	p.Tyr403Cys	missense_variant	12/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000458637.6	c.1208A>G	p.Tyr403Cys	missense_variant	12/49	1		ENSP00000392185	P1
MYO7A	ENST00000409619.6	c.1175A>G	p.Tyr392Cys	missense_variant	13/50	1		ENSP00000386635

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the MYO7A protein (p.Tyr403Cys). This variant is present in population databases (rs797044511, gnomAD 0.001%). This missense change has been observed in individual(s) with Usher syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 178667). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2017	- -

Usher syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Dec 21, 2022

The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). 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 Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 12, 2013

The Tyr403Cys in MYO7A has been identified in two siblings with clinical feature s of Usher syndrome by our laboratory. Both siblings carried a second MYO7A vari ant on the other MYO7A allele. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest tha t the Tyr403Cys variant may impact the protein. In summary, this variant is like ly to be pathogenic, though additional studies are required to fully establish i ts clinical significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Feb 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.7	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.79		Loss of MoRF binding (P = 0.1165);Loss of MoRF binding (P = 0.1165);Loss of MoRF binding (P = 0.1165);.;
MVP		0.97
MPC		0.52
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.92

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

Other links and lift over

dbSNP: rs797044511; hg19: chr11-76872026;