11-77211162-A-G

Position:

• chr11-77211162-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PM3 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID:21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022).1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576905/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2
• Conservation: PhyloP100: 7.06

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 Likely_pathogenic. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6062A>G	p.Lys2021Arg	missense_variant	45/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6062A>G	p.Lys2021Arg	missense_variant	45/49	1	NM_000260.4	ENSP00000386331

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426868 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 705974

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: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome type 1 Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jan 18, 2023	The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID: 21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022). 1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -

Usher syndrome type 1B Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 05, 2015

The p.Lys2021Arg variant in MYO7A has been reported in one individual with type I Usher syndrome who was compound heterozygous for a second likely pathogenic va riant in MYO7A (Roux 2011). This variant was absent from large population studie s. Computational prediction tools and conservation analyses suggest that the p.L ys2021Arg variant may impact the protein. In summary, although additional studie s are required to fully establish its clinical significance, this variant is lik ely pathogenic based on the previous report in an individual with Usher syndrome . -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 18, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 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: 21436283) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Benign	0.044	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.75
MutPred		0.50		Loss of methylation at K2021 (P = 0.0092);.;.;.;
MVP		0.89
MPC		0.42
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.84
gMVP		0.65

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

Other links and lift over

dbSNP: rs876657655; hg19: chr11-76922207;