rs868979094

Variant names:

• chr11-77160199-C-T
• rs868979094
• NM_000260.4:c.1117C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000260.4(MYO7A):​c.1117C>T​(p.Arg373Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000351 in 1,425,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 4.06
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77160200-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1196532.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-77160199-C-T is Pathogenic according to our data. Variant chr11-77160199-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228997.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1117C>T	p.Arg373Cys	missense_variant	Exon 11 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1117C>T	p.Arg373Cys	missense_variant	Exon 11 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1117C>T	p.Arg373Cys	missense_variant	Exon 11 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.1084C>T	p.Arg362Cys	missense_variant	Exon 12 of 50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 191070 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1425190 Hom.: 0 Cov.: 31 AF XY: 0.00000425 AC XY: 3 AN XY: 705470

African (AFR) AF: 0.0000308 AC: 1 AN: 32512

American (AMR) AF: 0.00 AC: 0 AN: 39762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 37296

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1094250

Other (OTH) AF: 0.00 AC: 0 AN: 59032

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000819 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:2

Jun 04, 2016

Hereditary Research Laboratory, Bethlehem University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

severe-profound -

Aug 01, 2020

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

MYO7A c.1117C>T, p.R373C alters a completely conserved residue of MYO7A in all sequenced vertebrates. The variant is homozygous in 8 Palestinian children from an extended kindred with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. -

not provided Pathogenic:1 Uncertain:1

Sep 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the MYO7A protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal recessive non-syndromic deafness (PMID: 22903915, 30733538, 32467589, 32747562). ClinVar contains an entry for this variant (Variation ID: 228997). 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. For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO7A: PM2, PP1, PP3 -

Usher syndrome Pathogenic:1

Apr 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO7A c.1117C>T (p.Arg373Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-06 in 1425190 control chromosomes. c.1117C>T has been reported in the literature in multiple individuals affected with Usher Syndrome in the homozygous state and segregated with disease in at least one family (e.g. Babanejad_2012, AbuRayyan_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32747562, 22903915). ClinVar contains an entry for this variant (Variation ID: 228997). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg373Cys variant in MYO7A has been reported in 2 Iranian siblings with hearing loss, bot h of whom were homozygous for the variant (Babanejad 2012). Data from large popu lation studies is insufficient to assess the frequency of this variant; however, the variant was reportedly not identified in 200 Iranian chromosomes (Babanejad 2012). Computational prediction tools and conservation analysis suggest that th is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg373Cys variant is uncerta in. -

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

Nov 28, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.8	H;.;H;.
PhyloP100		4.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D;.;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.92
MutPred		0.82		Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);Loss of disorder (P = 0.0437);.;
MVP		0.96
MPC		0.52
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.80
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs868979094; hg19: chr11-76871245;