rs45629132

Positions:

• chr11-77159450-G-A
• chr11-77159450-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_Supporting BP2

This summary comes from the ClinGen Evidence Repository: The c.1007G>A (p.Arg336His) variant in MYO7A was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID:16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA132194/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:10
• Conservation: PhyloP100: 7.72

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_benign. Variant got -2 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1007G>A	p.Arg336His	missense_variant	10/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1007G>A	p.Arg336His	missense_variant	10/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000458637.6	c.1007G>A	p.Arg336His	missense_variant	10/49	1		ENSP00000392185	P1
MYO7A	ENST00000409619.6	c.974G>A	p.Arg325His	missense_variant	11/50	1		ENSP00000386635

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 210 AN: 129680 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000931

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000904

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00261

Gnomad OTH AF: 0.000559

GnomAD3 exomes AF: 0.00116 AC: 288 AN: 247514 Hom.: 1 AF XY: 0.00105 AC XY: 141 AN XY: 134430

Gnomad AFR exome AF: 0.000713

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.00234 AC: 2822 AN: 1204636 Hom.: 4 Cov.: 35 AF XY: 0.00230 AC XY: 1372 AN XY: 597724

Gnomad4 AFR exome AF: 0.000556

Gnomad4 AMR exome AF: 0.000578

Gnomad4 ASJ exome AF: 0.000171

Gnomad4 EAS exome AF: 0.0000423

Gnomad4 SAS exome AF: 0.0000479

Gnomad4 FIN exome AF: 0.000407

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00162 AC: 210 AN: 129732 Hom.: 0 Cov.: 29 AF XY: 0.00151 AC XY: 92 AN XY: 61010

Gnomad4 AFR AF: 0.000930

Gnomad4 AMR AF: 0.000902

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000246

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.00261

Gnomad4 OTH AF: 0.000555

Alfa AF: 0.00187 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00193 AC: 16

ExAC AF: 0.00115 AC: 139

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00166

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2020	This variant is associated with the following publications: (PMID: 30311386, 30245029, 15221449, 16470552, 25262649) -

Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 24, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3. -

Usher syndrome type 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 04, 2021	NM_000260.3(MYO7A):c.1007G>A(R336H) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R336H has been observed in cases with relevant disease (PMID: 23804846, 16470552, 33363762). Functional assessments of this variant are not available in the literature. R336H has been observed in population frequency databases (gnomAD: NFE 0.22%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.1007G>A(R336H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2015	p.Arg336His in exon 10 of MYO7A: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (125/66438) of European chrom osomes including 1 homozygous individual by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs45629132). This variant has been re ported in the literature; however, there is no evidence to support pathogenicity . It was identified in a family with autosomal dominant hearing loss but found n ot to segregate with disease and therefore assumed to be benign (Luijendijk 2004 ). It was also identified in the heterozygous state in a proband with Usher synd rome without a second variant (Jaijo 2006). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2016	- -

Meniere disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Dec 14, 2020

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Nov 02, 2020

The c.1007G>A (p.Arg336His) variant in MYO7A was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID: 16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2. -

Usher syndrome type 1B Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 16, 2020

- -

MYO7A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.099	T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.97	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N;.;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.069	T;.;T;T
Sift4G	Benign	0.070	T;T;T;T
Polyphen		0.99	D;.;.;.
Vest4		0.83
MVP		0.95
MPC		0.11
ClinPred		0.027	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45629132; hg19: chr11-76870496; COSMIC: COSV68684980;