rs797044491

chr11-77158404-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000260.4(MYO7A):c.977T>A(p.Leu326Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:3
• Conservation: PhyloP100: 8.02

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-77158404-T-A is Pathogenic according to our data. Variant chr11-77158404-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164664.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.977T>A	p.Leu326Gln	missense_variant	9/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.977T>A	p.Leu326Gln	missense_variant	9/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.977T>A	p.Leu326Gln	missense_variant	9/49	1		P1
MYO7A	ENST00000409619.6	c.944T>A	p.Leu315Gln	missense_variant	10/50	1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460228 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726422

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	Observed with no second variant in an individual with hearing loss in published literature (Le Quesne Stabej et al., 2012); Not observed in large population cohorts (Lek et al., 2016); 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: 18181211, 22135276) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 326 of the MYO7A protein (p.Leu326Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome (PMID: 18181211). ClinVar contains an entry for this variant (Variation ID: 164664). 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. This variant disrupts the p.Leu326 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 25558175), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Usher syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 23, 2020

The c.977T>A (p.Leu326Gln) variant in MYO7A was absent from gnomAD v2.1.1 (PM2).This variant has been detected in at least 2 probands with Usher syndrome. For 1 of those patients, a pathogenic or suspected-pathogenic variants was observed in trans, and in 1 the variant was observed in the homozygous state (PM3; SCV000199549.4, PMID:18181211; ClinVar ID: 164663). At least one of these probands was confirmed to have both hearing loss and retinitis pigmentosa, features highly specific for Usher syndrome (PP4). The REVEL computational prediction tool produced a score of 0.991, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP3, PP4). -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2013

The Leu326Gln variant in MYO7A has been reported in two individuals with clinica l features of Usher syndrome, one of whom was homozygous ( Riazuddin 2008, Le Qu esne Stabej 2012). In addition, this variant was identified in trans with a seco nd pathogenic MYO7A variant in this individual, supporting a likely pathogenic r ole. Furthermore, computational analyses (biochemical amino acid properties, con servation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact t he protein. In summary, this variant is likely to be pathogenic, though addition al studies are required to fully establish its clinical significance. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 10, 2021

NM_000260.3(MYO7A):c.977T>A(L326Q) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. L326Q has been observed in cases with relevant disease (PMID: 22135276, 18181211, 33269433, 30303587). Functional assessments of this variant are not available in the literature. L326Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.977T>A(L326Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

MYO7A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 13, 2017

The MYO7A c.977T>A (p.Leu326Gln) missense variant has been reported in two studies in which it is found in two individuals with MYO7A-Related Disorders. The p.Leu326Gln variant was found in a homozygous state in one individual with Usher syndrome and in a heterozygous state (with a presumed unknown second allele) in one individual with atypical Usher syndrome (Riazuddin et al. 2008; Le Quesne Stabej et al. 2012). The p.Leu326Gln variant was absent from 1164 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database and is in a region of good sequence coverage, so the variant is presumed to be rare. Another variant with a different amino acid change at the same residue (p.Leu326Pro) has also been detected in an individual with type 1 Usher syndrome in a compound heterozygous state (Sodi et al. 2014). This variant has not been reported in association with autosomal dominant or autosomal recessive nonsyndromic hearing loss. Based on the evidence, the p.Leu326Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;.;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.92		Loss of stability (P = 0.0359);Loss of stability (P = 0.0359);Loss of stability (P = 0.0359);.;
MVP		0.98
MPC		0.48
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797044491; hg19: chr11-76869450;