rs397516332

Variant names:

• chr11-77214608-G-A
• rs397516332
• NM_000260.4:c.6560G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77214608-G-A
• chr11-77214608-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PM3 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.6560G>A variant in MYO7A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 2187. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001190 (1/84018 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.915, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A (PP3). At least one patient with this variant displayed profound congenital deafness and retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10930322). This variant has been detected in at least two individuals with Usher syndrome. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant published by multiple submitters in ClinVar (c.2904G>T (p.Glu968Asp) and c.3719G>A (p.R1240Q)) and both of those were presumed in trans (1 PM3 point, PMID:10930322, LMM) (PM3). In summary, this variant was reviewed by the ClinGen Hearing Loss VCEP and classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278713/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense, splice_region
• Scores: Splicing: ADA: 0.9759
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.55
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 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.
• 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 rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6560G>A	p.Gly2187Asp	missense_variant, splice_region_variant	Exon 49 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6560G>A	p.Gly2187Asp	missense_variant, splice_region_variant	Exon 49 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6440G>A	p.Gly2147Asp	missense_variant, splice_region_variant	Exon 49 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6413G>A	p.Gly2138Asp	missense_variant, splice_region_variant	Exon 50 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3986G>A	p.Gly1329Asp	missense_variant, splice_region_variant	Exon 29 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*1132G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 32 of 32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*1132G>A		3_prime_UTR_variant	Exon 32 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000516 AC: 1 AN: 193940 AF XY: 0.00000966

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1421464 Hom.: 0 Cov.: 30 AF XY: 0.00000284 AC XY: 2 AN XY: 703422

African (AFR) AF: 0.00 AC: 0 AN: 32526

American (AMR) AF: 0.00 AC: 0 AN: 38714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 37752

South Asian (SAS) AF: 0.00 AC: 0 AN: 80618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1090516

Other (OTH) AF: 0.00 AC: 0 AN: 59162

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000832 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:2

Aug 03, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.6560G>A variant in MYO7A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 2187. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001190 (1/84018 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.915, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A (PP3). At least one patient with this variant displayed profound congenital deafness and retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10930322). This variant has been detected in at least two individuals with Usher syndrome. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant published by multiple submitters in ClinVar (c.2904G>T (p.Glu968Asp) and c.3719G>A (p.R1240Q)) and both of those were presumed in trans (1 PM3 point, PMID:10930322, LMM) (PM3). In summary, this variant was reviewed by the ClinGen Hearing Loss VCEP and classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). -

Mar 13, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly2187Asp variant in MYO7A has been reported in 1 individual with Usher syndrome (Bharadwaj 2000) and identified by our laboratory in 1 individual with profound congenital hearing loss and vestibular problems. Both individuals were compound heterozygous for a second pathogenic or likely pathogenic MYO7A variant. This variant has been identified in 0.001% (1/84018) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516332). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Gly2187Asp variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly2187Asp variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP3 -

Usher syndrome type 1B Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Apr 13, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.70		Gain of relative solvent accessibility (P = 0.09);.;.;.;
MVP		0.97
MPC		0.53
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.77
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

Other links and lift over

dbSNP: rs397516332; hg19: chr11-76925653;