11-77172799-T-C

Position:

chr11-77172799-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP1_StrongPM3PP3

This summary comes from the ClinGen Evidence Repository: The c.1849T>C variant in MYO7A is a missense variant predicted to cause substitution of serine by proline at amino acid 617 (p.Ser617Pro). The highest population minor allele frequency in gnomAD v4 is 0.00009496 (8/84244 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with nonsyndromic hearing loss. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (c.20G>T [p.Gly7Val], c.1258A>T [p.K420*], 2 PM3 points, PMIDs: 30303587, 33187236). One individual was homozygous for the variant (0.5 PM3 points, PMIDs: 27344577, 33671976) (PM3). The variant has been reported to segregate with nonsyndromic hearing loss in 7 affected family members from 3 families (PP1_Strong; PMIDs: 27344577, 30303587, 33187236, 33671976). This variant has also been detected in 1 individual with Usher syndrome, with a second variant c.4838delA (p.Asp1613ValfsTer32) without phase confirmation (PMIDs: 28041643, 32581362). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PM3, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024). As cases have been observed with both nonsyndromic hearing loss and Usher syndrome and genotype-phenotype correlation is currently unclear, individuals should be evaluated for both conditions. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6197628/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:1

Conservation

PhyloP100: 7.57

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 Likely_pathogenic. Variant got 7 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.1849T>C	p.Ser617Pro	missense_variant	16/49	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.1849T>C	p.Ser617Pro	missense_variant	16/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.1849T>C	p.Ser617Pro	missense_variant	16/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.1816T>C	p.Ser606Pro	missense_variant	17/50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000669443.1 linkuse as main transcript	c.211T>C	p.Ser71Pro	missense_variant	3/3			ENSP00000499530.1	A0A590UJR8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

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:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

163212

Hom.:

AF XY:

0.0000230

AC XY:

AN XY:

86810

show subpopulations

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 SAS exome

AF:

0.0000872

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000427

AC:

AN:

1405520

Hom.:

Cov.:

AF XY:

0.00000721

AC XY:

AN XY:

693888

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000755

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000910

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:2

Pathogenic, no assertion criteria provided	research	National Institute on Deafness and Communication Disorders, National Institutes of Health	Jul 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYO7A related disorder (ClinVar ID: VCV000438172 / PMID: 28041643). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33187236) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33187236). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Usher syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 28, 2024

The c.1849T>C variant in MYO7A is a missense variant predicted to cause substitution of serine by proline at amino acid 617 (p.Ser617Pro). The highest population minor allele frequency in gnomAD v4 is 0.00009496 (8/84244 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with nonsyndromic hearing loss. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (c.20G>T [p.Gly7Val], c.1258A>T [p.K420*], 2 PM3 points, PMIDs: 30303587, 33187236). One individual was homozygous for the variant (0.5 PM3 points, PMIDs: 27344577, 33671976) (PM3). The variant has been reported to segregate with nonsyndromic hearing loss in 7 affected family members from 3 families (PP1_Strong; PMIDs: 27344577, 30303587, 33187236, 33671976). This variant has also been detected in 1 individual with Usher syndrome, with a second variant c.4838delA (p.Asp1613ValfsTer32) without phase confirmation (PMIDs: 28041643, 32581362). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PM3, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024). As cases have been observed with both nonsyndromic hearing loss and Usher syndrome and genotype-phenotype correlation is currently unclear, individuals should be evaluated for both conditions. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 617 of the MYO7A protein (p.Ser617Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive deafness, MYO7A-related conditions, and/or Usher syndrome type 1 (PMID: 28041643, 30303587, 33671976; 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: 438172). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.3

H;.;H;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.6

D;.;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.95

MutPred

0.81

Loss of phosphorylation at S617 (P = 0.0546);Loss of phosphorylation at S617 (P = 0.0546);Loss of phosphorylation at S617 (P = 0.0546);.;

MVP

0.94

MPC

0.52

ClinPred

0.99

GERP RS

4.8

Varity_R

0.98

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

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