rs111033215

chr11-77206108-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000260.4(MYO7A):c.5648G>A(p.Arg1883Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,222 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1883W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.59

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain MyTH4 2 (size 149) in uniprot entity MYO7A_HUMAN there are 35 pathogenic changes around while only 11 benign (76%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77206107-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1194353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 11-77206108-G-A is Pathogenic according to our data. Variant chr11-77206108-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77206108-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-77206108-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.5648G>A	p.Arg1883Gln	missense_variant	41/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.5648G>A	p.Arg1883Gln	missense_variant	41/49	1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000326 AC: 8 AN: 245768 Hom.: 0 AF XY: 0.0000300 AC XY: 4 AN XY: 133456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460026 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74414

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

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: 0.000164 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1883 of the MYO7A protein (p.Arg1883Gln). This variant is present in population databases (rs111033215, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 20844544, 21569298, 21873662, 22135276). 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: 43294). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	The R1883Q missense variant in the MYO7A gene has been reported previously in association with Usher syndrome type IB, and has been reported in trans with a pathogenic variant on the opposite allele (in trans) in multiple individuals (Ouyang et al., 2005; Nakanishi et al., 2010; Bonnet et al., 2011; Le Quesne Stabej et al., 2012). The R1883Q variant is observed in 3/34194 (0.009%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The R1883Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We classify this variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Usher syndrome type 1 Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Refractive Surgery Department, Bright Eye Hospital	May 13, 2022	WES identified two novel compound heterozygous mutations (c.5648G>A(rs111033215) and c.6238-1G>C) in MYO7A in two patients with Usher syndrome type 1. We found that the mutation c.5648G>A was predicted as “Probably Damaging” by the PolyPhen2 analysis. It was also evaluated as “Deleterious” and “Disease Causing” by other prediction programs (SIFT, PROVEIN, MutationTaster). Thus, the mutation of c.5648G>A was potentially pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jan 16, 2018

- -

Usher syndrome type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2018

The p.Arg1883Gln variant in MYO7A has been reported in 4 individuals with Usher Syndrome Type I (USH1), all of whom also carried a second pathogenic variant (Ou yang 2005, Nakanishi 2010, Bonnet 2011, Le Quesne Stabej 2012, Jacobson 2011). T he p.Arg1883Gln variant has been identified in 0.0088% (3/34194) Latino chromoso mes and 0.004% (10/274046) of total chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033215). Although this variant has been seen in the general population, its overall frequency is low en ough to be consistent with a recessive carrier frequency. Computational predicti on tools and conservation analysis suggest that the p.Arg1883Gln variant may imp act the protein. In summary, this variant meets criteria to be classified as pat hogenic for autosomal recessive Usher syndrome based upon multiple occurrences a s a compound heterozygous variant with pathogenic variants in the same gene in i ndividuals with Usher syndrome, low frequency in the gnomAD database, and predic ted impact on protein. ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supportin g, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.93
MVP		0.96
MPC		0.42
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.95
gMVP		0.87

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: rs111033215; hg19: chr11-76917153;