11-77211329-TG-TGG

Variant names:

• chr11-77211329-T-TG
• rs730880367
• NM_000260.4:c.6231dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000260.4(MYO7A):​c.6231dupG​(p.Lys2078GlufsTer50) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO7A NM_000260.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.52

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-77211329-T-TG is Pathogenic according to our data. Variant chr11-77211329-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 179745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6231dupG	p.Lys2078GlufsTer50	frameshift_variant	Exon 45 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6231dupG	p.Lys2078GlufsTer50	frameshift_variant	Exon 45 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6117dupG	p.Lys2040GlufsTer48	frameshift_variant	Exon 45 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6084dupG	p.Lys2029GlufsTer50	frameshift_variant	Exon 46 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3657dupG	p.Lys1220GlufsTer50	frameshift_variant	Exon 25 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*803dupG		non_coding_transcript_exon_variant	Exon 28 of 32			ENSP00000499323.1
MYO7A	ENST00000670577	n.*803dupG		3_prime_UTR_variant	Exon 28 of 30			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 179745). This premature translational stop signal has been observed in individual(s) with autosomal recessive MYO7A-related conditions (PMID: 28944237, 29048421). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2078Glufs*50) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). -

Usher syndrome type 1 Pathogenic:1

Aug 24, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM2_SUP,PM3 -

Rare genetic deafness Pathogenic:1

Jul 22, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys2078fs variant in MYO7A has been previously reported in one individual with hearing loss. It has not been identified in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 2078 and lead to a premature termination codon 50 amino acids downstream. This alteration is then predicted to lead to a trunca ted or absent protein. Truncating or loss of function variants in the MYO7A gen e are an established disease mechanism for Usher syndrome. In summary, this var iant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner (http://personalizedmedicine.partners.org/Laboratory- For-Molecular-Medicine/). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs730880367; hg19: chr11-76922374;