rs368657015

Positions:

chr11-77205554-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000260.4(MYO7A):c.5573T>C(p.Leu1858Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,340 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.64

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a domain MyTH4 2 (size 149) in uniprot entity MYO7A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_000260.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 11-77205554-T-C is Pathogenic according to our data. Variant chr11-77205554-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77205554-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-77205554-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.5573T>C	p.Leu1858Pro	missense_variant	40/49	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.5573T>C	p.Leu1858Pro	missense_variant	40/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.5459T>C	p.Leu1820Pro	missense_variant	40/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.5426T>C	p.Leu1809Pro	missense_variant	41/50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 linkuse as main transcript	c.2999T>C	p.Leu1000Pro	missense_variant	20/29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 linkuse as main transcript	n.*171T>C		non_coding_transcript_exon_variant	23/32			ENSP00000499323.1	A0A590UJ94
MYO7A	ENST00000670577.1 linkuse as main transcript	n.*171T>C		3_prime_UTR_variant	23/32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

245616

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

133480

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000538

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1460152

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726158

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000801

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1858 of the MYO7A protein (p.Leu1858Pro). This variant is present in population databases (rs368657015, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 16679490, 22135276, 28944237). 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: 43288). 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -

MYO7A-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 11, 2024	The MYO7A c.5573T>C variant is predicted to result in the amino acid substitution p.Leu1858Pro. This variant has been reported in the homozygous state or heterozygous state with a second MYO7A variant in multiple individuals with typical or atypical Usher syndrome (Bharadwaj. 2000. PubMed ID: 10930322; Roux et al. 2006. PubMed ID: 16679490; Jacobson et al. 2008. PubMed ID: 18463160; Roux et al. 2011. PubMed ID: 21436283; Le Quesne Stabej et al. 2012. PubMed ID: 22135276; Bademci. 2016. PubMed ID: 26226137; Neuhaus. 2017. PubMed ID: 28944237; Khateb et al. 2019. PubMed ID: 31479088; Bahena et al. 2021. PubMed ID: 34148116). In an least one of the reported individuals, the variant was confirmed to be in trans with a second causative variant (Bademci. 2016. PubMed ID: 26226137). This variant is reported in 0.0055% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/43288). Taken together, this variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 14, 2017	Variants in the MYO7A gene are known to cause MYO7A-related disorders, which include Usher syndrome and autosomal recessive and autosomal dominant forms of nonsyndromic hearing loss. The c.5573T>C (p.Leu1858Pro) variant has been identified in a compound heterozygous state in at least six affected individuals, including five with Usher syndrome type 1 and one with autosomal recessive nonsyndromic hearing loss (Roux et al. 2006; Jacobson et al. 2008; Roux et al. 2011; Le Quesne Stabej et al. 2012; Bademci et al. 2016). One additional individual with Usher syndrome type 1 was heterozygous for the p.Leu1858Pro variant and another missense variant, but the phase of the variants was unclear (Bharadwaj et al. 2000). The variant has not been reported in conjunction with autosomal dominant nonsyndromic hearing loss. The p.Leu1858Pro variant was absent from 2148 control chromosomes and is reported at a frequency of 0.000056 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Leu1858Pro variant is classified as pathogenic for MYO7A-related disorders. Note: While the p.Leu1858Pro variant has not been reported in conjunction with autosomal dominant nonsyndromic hearing loss, disease risk cannot be ruled out. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Usher syndrome type 1B

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2016

The p.Leu1858Pro variant in MYO7A has been reported in at least 10 probands with Usher syndrome who were either homozygous for the variant or compound heterozyg ous with a second pathogenic or likely pathogenic variant in MYO7A (Bharadwaj 20 00, Roux 2006, Jacobson 2008, Blanchet 2007, Roux 2011, LeQuesne Stabej 2012, LM M data). It has been identified in 3/55658 European chromosomes by the Exome Agg regation Consortium (http://exac.broadinstitute.org/; dbSNP rs368657015), which is low enough to be consistent with the carrier frequency in the general populat ion. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based on its presence in homozyg osity or compound heterozygosity with a second pathogenic allele in many individ uals with Usher syndrome, and low frequency in the general population. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.5

M;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.0

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.93

MVP

0.96

MPC

0.57

ClinPred

0.93

GERP RS

3.7

Varity_R

0.99

gMVP

0.92

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

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