chr11-77184715-G-A

Position:

• chr11-77184715-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5 PM2 PP3 PP4 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.3503G>A (p.Arg1168Gln) variant in MYO7A has been detected in at least 4 probands with Usher syndrome. For two of those probands, a pathogenic or suspected-pathogenic variants was observed in trans, and in one individual, the variant was observed with a pathogenic or suspected-pathogenic variant, but it was unclear if phasing was performed (PM3_Strong, PP4; PMID:25404053, 27460420, 28944237). The allele frequency of this variant is 0.004%% (1/26850) of South Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The c.3503G>A (p.Arg1168Gln) variant is located in the last base of the exon, which is part of the 5’ consensus sequence, and computational tools suggest an impact to splicing. Furthermore, tThe REVEL computational prediction analysis tool produced a score of 0.9, which is above the threshold necessary to apply PP3. A different likely pathogenic or suspected-pathogenic variant at the same nucleotide (c.3503G>C, Arg1168Pro) has been previously identified in an individual with Usher syndrome who was compound heterozygous for a second pathogenic truncating variant (PMID:16470552). In addition, a minigene assay demonstrated that the 3503G>C variant led to skipping of exon 27 (PMID:20052763) suggesting that variants that alter the c.3503G nucleotide may cause abnormal splicing (PM5_Supporting). 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: PM3_Strong, PP4, PM2, PP3, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA184505/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 9.55

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 10 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.
• PM5: 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.3503G>A	p.Arg1168Gln	missense_variant, splice_region_variant	27/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3503G>A	p.Arg1168Gln	missense_variant, splice_region_variant	27/49	1	NM_000260.4	ENSP00000386331

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000508 AC: 1 AN: 196868 Hom.: 0 AF XY: 0.00000932 AC XY: 1 AN XY: 107348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000372

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1437552 Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 8 AN XY: 713624

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2023	Variant summary: MYO7A c.3503G>A (p.Arg1168Gln) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence . This variant also locates in the last base of exon 27, which is part of the 5' consensus splice region. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the 5 splicing donor site. Two predict the variant weakens the 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-06 in 196868 control chromosomes in gnomAD. c.3503G>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including being compound heterozygous state with five different pathogenic/likely pathogenic variants in at-least five Usher Syndrome cases and being homozygous in at-least one Usher Syndrome case (example: Aparisi_2014, Dad_2016, Fuster-Garcia_2018, Neuhaus_2017, Weisschuh_2020). These data indicate that the variant is very 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: 25404053, 27957503, 30459346, 28944237, 32531858). Five submitters including the ClinGen Hearing Loss Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 16, 2019	The c.3503G>A (p.Arg1168Gln) variant in MYO7A has been detected in at least 4 probands with Usher syndrome. For two of those probands, a pathogenic or suspected-pathogenic variants was observed in trans, and in one individual, the variant was observed with a pathogenic or suspected-pathogenic variant, but it was unclear if phasing was performed (PM3_Strong, PP4; PMID:25404053, 27460420, 28944237). The allele frequency of this variant is 0.004%% (1/26850) of South Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The c.3503G>A (p.Arg1168Gln) variant is located in the last base of the exon, which is part of the 5' consensus sequence, and computational tools suggest an impact to splicing. Furthermore, tThe REVEL computational prediction analysis tool produced a score of 0.9, which is above the threshold necessary to apply PP3. A different likely pathogenic or suspected-pathogenic variant at the same nucleotide (c.3503G>C, Arg1168Pro) has been previously identified in an individual with Usher syndrome who was compound heterozygous for a second pathogenic truncating variant (PMID: 16470552). In addition, a minigene assay demonstrated that the 3503G>C variant led to skipping of exon 27 (PMID: 20052763) suggesting that variants that alter the c.3503G nucleotide may cause abnormal splicing (PM5_Supporting). 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: PM3_Strong, PP4, PM2, PP3, PM5_Supporting. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1168 of the MYO7A protein (p.Arg1168Gln). This variant also falls at the last nucleotide of exon 27, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Usher syndrome (PMID: 25404053, 27460420, 28944237). ClinVar contains an entry for this variant (Variation ID: 179479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 03, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2016

- -

MYO7A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The MYO7A c.3503G>A variant is predicted to result in the amino acid substitution p.Arg1168Gln. This variant was reported along with a second causative variant in multiple individuals with Usher syndrome or retinal degeneration (Aparisi et al. 2014. PubMed ID: 25404053; Table S1, Bonnet et al. 2016. PubMed ID: 27460420; Neuhaus et al. 2017. PubMed ID: 28944237; Table S1, Khateb et al. 2020. PubMed ID: 31479088; Table S2, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.0037% of alleles in individuals of South Asian descent in gnomAD and is interpreted by the ClinGen Hearing Loss Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/179479/). This variant is interpreted as pathogenic -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The 3503G>A (Ar g1168Gln) variant in MYO7A has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the f requency of this variant. This variant is located in the last base of exon 27 in the major transcript (NM_000260.3) of MYO7A, which is part of the conserved 5? splice region of intron 27. Computational tools suggest an impact to splicing; h owever, this information is not predictive enough to determine pathogenicity. Ho wever, a different variant at the same nucleotide (3503G>C, Arg1168Pro) has been previously described in an individual with Usher syndrome who was compound hete rozygous for a second pathogenic variant (Jaijo 2006). Functional studies demons trated that the 3503G>C variant led to skipping of exon 27 (Le Guedard-Mereuze 2 010), suggesting that variants that alter the c.3503G nucleotide cause abnormal splicing. In summary, the clinical significance of this variant cannot be determ ined with certainty; however based upon its location within the splice consensus sequence and its predicted impact on splicing, we would lean towards a more lik ely pathogenic role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;T;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D;D;D;.;D
Sift4G	Uncertain	0.056	T;T;T;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.94
MVP		0.96
MPC		0.50
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.76
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs797044516; hg19: chr11-76895760; COSMIC: COSV68685006;