rs1555090368

Variant names:

• chr11-77189425-GTC-G
• rs1555090368
• NM_000260.4:c.3591_3592delCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000260.4(MYO7A):​c.3591_3592delCT​(p.Cys1198ArgfsTer30) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.56
• Publications: 0 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

ENSG00000296534 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 11-77189425-GTC-G is Pathogenic according to our data. Variant chr11-77189425-GTC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228378.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.3591_3592delCT	p.Cys1198ArgfsTer30	frameshift_variant	Exon 28 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3591_3592delCT	p.Cys1198ArgfsTer30	frameshift_variant	Exon 28 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3591_3592delCT	p.Cys1198ArgfsTer30	frameshift_variant	Exon 28 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3558_3559delCT	p.Cys1187ArgfsTer30	frameshift_variant	Exon 29 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1134_1135delCT	p.Cys379ArgfsTer30	frameshift_variant	Exon 8 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1431_1432delCT		non_coding_transcript_exon_variant	Exon 11 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249164 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: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 27, 2023

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: 228378). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 26355662). This variant is present in population databases (rs797044564, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Cys1198Argfs*30) 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). -

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Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Usher syndrome Pathogenic:1

Dec 31, 2022

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Rare genetic deafness Pathogenic:1

May 28, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys1198fs variant in MYO7A has not been previously reported in individuals with hearing loss or Usher syndrome or in large population studies, though the ability of these studies to accurately detect indels may be limited. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 1198 and leads to a premature termination codon 30 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating or loss of function variants in the MYO7A gene ar e an established disease mechanism for Usher syndrome. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an auto somal recessive manner based on its predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555090368; hg19: chr11-76900470;