rs1555090294

chr11-77189386-C-Achr11-77189386-C-T

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.3546C>A(p.Asn1182Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,540 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. N1182S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 0.445

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain 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 chr11-77189385-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2979938.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 11-77189386-C-A is Pathogenic according to our data. Variant chr11-77189386-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438177.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-77189386-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.3546C>A	p.Asn1182Lys	missense_variant	28/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.3546C>A	p.Asn1182Lys	missense_variant	28/49	1	NM_000260.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727028

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2023	Variant summary: MYO7A c.3546C>A (p.Asn1182Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249032 control chromosomes. c.3546C>A has been reported in the literature in individuals affected with Usher Syndrome. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 31479088, 26654877). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=1, likely pathogenic n=2, pathogenic n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jun 27, 2023	The p.Asn1182Lys variant in MYO7A is a missense variant predicted to cause substitution of asparagine to lysine at amino acid 1182. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.833 which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own (PP3). This variant has been detected in at least four probands with AR Usher syndrome. Two patients were homozygous for the variant, while the other two were compound heterozygous with a pathogenic or likely pathogenic variant; however only one was confirmed trans (c.721C>T (p.Arg241Cys), 2.0 PM3_Strong points, PMID:27460420, 28041643, 31479088, Invitae Internal Data (SCV001211338.4)). At least one patient with a variant identified in this gene displayed sensorineural hearing loss and retinitis pigmentosa, features consistent with Usher syndrome (PP4). The variant has been reported to segregate with AR Usher syndrome in 1 affected family member from 1 family (PP1; PMID: 31479088). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Strong, PP1, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2023	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1182 of the MYO7A protein (p.Asn1182Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Usher syndrome (PMID: 27460420, 28041643; Invitae). ClinVar contains an entry for this variant (Variation ID: 438177). 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. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28041643, 31479088, 27460420, 32581362) -

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	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.76		Gain of methylation at N1182 (P = 0.0076);Gain of methylation at N1182 (P = 0.0076);.;.;
MVP		0.96
MPC		0.50
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.94
gMVP		0.85

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: rs1555090294; hg19: chr11-76900431;