rs868979094

Positions:

• chr11-77160199-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 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).

• 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:4 U:3
• Conservation: PhyloP100: 4.06

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 228997.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1117C>T	p.Arg373Cys	missense_variant	11/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1117C>T	p.Arg373Cys	missense_variant	11/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000458637.6	c.1117C>T	p.Arg373Cys	missense_variant	11/49	1		ENSP00000392185	P1
MYO7A	ENST00000409619.6	c.1084C>T	p.Arg362Cys	missense_variant	12/50	1		ENSP00000386635

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	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. -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	severe-profound -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MYO7A: PM2, PP1, PP3 -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 23, 2024

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 18, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 28, 2017

- -

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;.
MutationTaster	Benign	1.0	D;D;D;D
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

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: rs868979094; hg19: chr11-76871245;