chr11-77172796-C-T

Position:

• chr11-77172796-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000260.4(MYO7A):​c.1846C>T​(p.Arg616Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,558,958 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 2.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1846C>T	p.Arg616Trp	missense_variant	16/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1846C>T	p.Arg616Trp	missense_variant	16/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1846C>T	p.Arg616Trp	missense_variant	16/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.1813C>T	p.Arg605Trp	missense_variant	17/50	1		ENSP00000386635.2
MYO7A	ENST00000669443.1	c.208C>T	p.Arg70Trp	missense_variant	3/3			ENSP00000499530.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 21 AN: 164936 Hom.: 0 AF XY: 0.000148 AC XY: 13 AN XY: 87696

Gnomad AFR exome AF: 0.000117

Gnomad AMR exome AF: 0.0000391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000311 AC: 437 AN: 1406720 Hom.: 0 Cov.: 31 AF XY: 0.000275 AC XY: 191 AN XY: 694538

Gnomad4 AFR exome AF: 0.000157

Gnomad4 AMR exome AF: 0.0000816

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.000377

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74364

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000538 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MYO7A: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2023	Observed in an individual with hearing loss in published literature; specific patient information is not available (Sommen et al., 2016); 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: 27068579, 34426522) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 616 of the MYO7A protein (p.Arg616Trp). This variant is present in population databases (rs369195493, gnomAD 0.03%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 43160). 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. -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2018	The p.Arg616Trp variant (rs369195493) has been previously identified in cohort of patients with suspected autosomal recessive hearing loss (Sommen 2016); however, no clinically relevant details were provided to independently assess the significance of this observation. This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 43160). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans populations of 0.03% (identified in 21 out of 79,010 chromosomes). The arginine at codon 616 is moderately conserved considering 13 species (Alamut software v2.9), although computational analyses suggest this variant has a significant effect on MYO7A protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Arg616Trp variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2017	The p.Arg616Trp variant in MYO7A has been reported in 2 individuals with sensori neural hearing loss and segregated with disease in one relative (Sommen 2016, LM M data). It has been identified in 4/9492 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369195493). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Arg616Trp is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	Variant summary: MYO7A c.1846C>T (p.Arg616Trp) 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 0.0003 in 1552046 control chromosomes (i.e. 464 heterozygotes) in the gnomAD database (v4 dataset). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MYO7A causing Usher Syndrome (0.0061), allowing no conclusion about variant significance. c.1846C>T has been reported in the literature in an individual affected with non-syndromic hearing loss (second variant not specified), and in a homozygous patient affected retinal dystrophy, which belong to the Usher syndrome phenotype spectrum (Sommen_2016, Iancu_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 43160). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 06, 2017

- -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2020

- -

MYO7A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2023

The MYO7A c.1846C>T variant is predicted to result in the amino acid substitution p.Arg616Trp. This variant was reported in an individual with non-syndromic hearing loss (Table S1, Sommen. 2016. PubMed ID: 27068579). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-76883842-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.0	M;.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;.;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.76
MVP		0.88
MPC		0.47
ClinPred		0.71	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.65

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: rs369195493; hg19: chr11-76883842;