rs372188355

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000260.4(MYO7A):c.218T>C(p.Leu73Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 1,598,996 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L73L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.218T>C	p.Leu73Pro	missense_variant	4/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.218T>C	p.Leu73Pro	missense_variant	4/49	1	NM_000260.4		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.218T>C	p.Leu73Pro	missense_variant	4/49	1		P1	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.185T>C	p.Leu62Pro	missense_variant	5/50	1			Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

1446864

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

718038

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000353

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000484

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 26, 2023

Variant summary: MYO7A c.218T>C (p.Leu73Pro) 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 4.5e-06 in 221926 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.218T>C has been reported in the literature in at least one compound heterozygous individual affected with autosomal recessive non-syndromic hearing loss (e.g., Sloan-Heggen_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26969326). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 31, 2018

- -

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 20, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces leucine with proline at codon 73 of the MYO7A protein (p.Leu73Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with autosomal recessive non-syndromic hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 556446). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.6

H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.2

D;.;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

1.0

MVP

0.97

MPC

0.59

ClinPred

1.0

GERP RS

4.9

Varity_R

0.98

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over