rs368341987

Variant names:

• chr11-77179843-G-A
• rs368341987
• NM_000260.4:c.2476G>A

Variant summary

Our verdict is Uncertain significance. Variant got -4 ACMG points: 4P and 8B. PP1 PP4 PM3 BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA180669/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00042 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00071 (3 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:10 B:1 O:1
• Conservation: PhyloP100: 8.14

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 Uncertain_significance. Variant got -4 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.2476G>A	p.Ala826Thr	missense_variant	Exon 21 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2476G>A	p.Ala826Thr	missense_variant	Exon 21 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2476G>A	p.Ala826Thr	missense_variant	Exon 21 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2443G>A	p.Ala815Thr	missense_variant	Exon 22 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.19G>A	p.Ala7Thr	missense_variant	Exon 1 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.316G>A		non_coding_transcript_exon_variant	Exon 4 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152256 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00661

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00121 AC: 170 AN: 139996 Hom.: 1 AF XY: 0.00162 AC XY: 123 AN XY: 75716

Gnomad AFR exome AF: 0.000292

Gnomad AMR exome AF: 0.0000816

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000939

Gnomad SAS exome AF: 0.00650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000711 AC: 989 AN: 1390456 Hom.: 3 Cov.: 31 AF XY: 0.000869 AC XY: 596 AN XY: 686182

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000559

Gnomad4 SAS exome AF: 0.00597

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000427

Gnomad4 OTH exome AF: 0.000708

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152374 Hom.: 2 Cov.: 34 AF XY: 0.000523 AC XY: 39 AN XY: 74512

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00662

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.000129 AC: 1

ExAC AF: 0.000974 AC: 78

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:10 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Dec 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000927011.1; PMID 30311386); This variant is associated with the following publications: (PMID: 18181211, 23770805, 34426522, 22135276, 33671976, 9382091, 27460420, 31479088, 29490346, 30245029, 31456290, 30881389, 37541188, 35551639, 38378725, 38219857, 30311386) -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 826 of the MYO7A protein (p.Ala826Thr). This variant is present in population databases (rs368341987, gnomAD 0.6%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Usher syndrome (PMID: 9382091, 29490346). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177732). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYO7A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Pathogenic:1 Uncertain:2

-

Baylor Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 24, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000260.3(MYO7A):c.2476G>A(A826T) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. A826T has been observed in cases with relevant disease (PMID: 9382091, 18181211, 22135276, 27460420, 29490346, 23770805, 30881389). Functional assessments of this variant are not available in the literature. A826T has been observed in population frequency databases (gnomAD: SAS 0.65%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.2476G>A(A826T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1 Uncertain:1

-

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A known pathogenic variants according to Deafness Variation Database and ClinVar based on PMID:9382091. This p.(Ala826Thr) variant was detected in an hearing impaired individual with a sloping audiogram, normal-to-severe HL, in compound heterozygosity with another known pathogenic variant, c.285+2T>G . -

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

Feb 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 01/15/2018 by GTR ID Blueprint Genetics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

MYO7A-related disorder Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYO7A c.2476G>A (p.Ala826Thr) missense variant has been reported in six studies in which it is found in a total of 19 patients with Usher syndrome including in 13 in a homozygous state, in five in a compound heterozygous state and in one in a heterozygous state (Adato et al. 1997; Riazuddin et al. 2008; Le Quesne Stabej et al. 2012; Shahzad et al. 2013; Vona et al. 2014; Bonnet et al. 2016). The p.Ala826Thr variant is present in a heterozygous state in two of 1214 control chromosomes and is reported at a frequency of 0.01471 in the Indian Telugu from the UK population of the 1000 Genomes project. The p.Ala826Thr variant is described as being located in the neck of the MYO7A protein within a motif whose sequence matches the consensus sequence of calmodulin-binding IQ motifs and is expected to impair the calmodulin chain-binding function of the protein. Based on the evidence, the p.Ala826Thr is classified as pathogenic for Usher Syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified Uncertain:1

Oct 03, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Usher syndrome Uncertain:1

Jan 18, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). -

Usher syndrome type 1B Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;.;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;T;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.0	L;.;L;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	D;.;N;N;.;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;.;D;D;.;D
Sift4G	Uncertain	0.0090	D;D;D;D;.;D
Polyphen		0.65	P;.;.;.;.;.
Vest4		0.50
MVP		0.92
MPC		0.15
ClinPred		0.059	T
GERP RS		4.5
Varity_R		0.51
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs368341987; hg19: chr11-76890889;