rs797044512

Positions:

• chr11-77156958-C-T

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.689C>T​(p.Ala230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,586 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.84

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]

MYO7A (HGNC:):

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, 0.984
• PP5: Variant 11-77156958-C-T is Pathogenic according to our data. Variant chr11-77156958-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 178993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77156958-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.689C>T	p.Ala230Val	missense_variant	7/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.689C>T	p.Ala230Val	missense_variant	7/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.689C>T	p.Ala230Val	missense_variant	7/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.656C>T	p.Ala219Val	missense_variant	8/50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 11 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 20, 2020	The p.Ala230Val missense variant has been reported to co-segregate with autosomal dominant non-syndromic progressive hearing loss in a large Italian family [PMID: 16449806]. The p.Ala230Val variant has also been reported in an unrelated 5-year old boy affected with moderate bilateral hearing loss [PMID: 28802369]. The variant is absent from the gnomAD database indicating that it is an extremely rare allele in the general population. The p.Ala230Val variant is predicted deleterious by various in silico prediction tools. The affected alanine residue is evolutionarily conserved and is located within the functionally important motor domain of MYO7A molecule. Missense variants in this region of the protein have been associated with autosomal dominant hearing loss. Based on the available evidence, the p.Ala230Val missense variant in the MYO7A gene is assessed as likely pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Feb 16, 2016	childhood onset, progressive HL, also myopia -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the MYO7A protein (p.Ala230Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 16449806, 28802369). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178993). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	Not observed 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: 28802369, 16449806) -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 12, 2016

- -

Bilateral sensorineural hearing impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo

-

pathogenic missense heterozygous variant was found to segregate with HL in six members of the same family -

MYO7A-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2023

The MYO7A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. This variant was reported to segregate with disease in a large family with autosomal dominant non-syndromic sensorineural hearing loss (Di Leva et al. 2006. PubMed ID: 16449806). This variant was also reported as de novo in an individual with moderate bilateral hearing loss (Kaneko et al. 2017. PubMed ID: 28802369). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2013

The Ala230Val variant in MYO7A has been reported in a large Italian pedigree aff ected with nonsyndromic post-lingual progressive hearing loss showing autosomal dominant inheritance(Di Leva 2006). The variant co-segregated with hearing loss in several affected family members, and was not identified in unaffected family members or in 200 ethnically matched control chromosomes (Di Leva 2006). In addi tion, this variant was not identified in large population studies. Furthermore, the alanine (Ala) residue at position 230 is located in the conserved motor doma in of the MYO7A protein. Missense variants in this region of the protein have be en associated with autosomal dominant hearing loss. In summary, this variant mee ts our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) b ased upon segregation analysis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.3	M;.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;.;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.98
MutPred		0.90		Gain of methylation at K231 (P = 0.0574);Gain of methylation at K231 (P = 0.0574);Gain of methylation at K231 (P = 0.0574);.;
MVP		0.87
MPC		0.47
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.87

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: rs797044512; hg19: chr11-76868004;