rs1555099541

Variant names:

• chr11-77198552-TTG-T
• rs1555099541
• NM_000260.4:c.4502_4503delTG

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.4502_4503delTG​(p.Val1501GlyfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.32

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 11-77198552-TTG-T is Pathogenic according to our data. Variant chr11-77198552-TTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77198552-TTG-T is described in Lovd as [Pathogenic]. Variant chr11-77198552-TTG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4502_4503delTG	p.Val1501GlyfsTer2	frameshift_variant	Exon 34 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4502_4503delTG	p.Val1501GlyfsTer2	frameshift_variant	Exon 34 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4502_4503delTG	p.Val1501GlyfsTer2	frameshift_variant	Exon 34 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4469_4470delTG	p.Val1490GlyfsTer2	frameshift_variant	Exon 35 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2045_2046delTG	p.Val682GlyfsTer2	frameshift_variant	Exon 14 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2342_2343delTG		non_coding_transcript_exon_variant	Exon 17 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461624 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 23, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the MYO7A gene demonstrated a two base pair deletion in exon 34, c.4502_4503del. This sequence change results in an amino acid frameshift and creates a premature stop codon one amino acid downstream of the change, p.Val1501Glyfs*2. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MYO7A protein with potentially abnormal function. This sequence change has been reported in a patient with Usher syndrome but no additional information was provided by the authors (PMID: 16963483). Other frameshift deletions in the MYO7A gene downstream to this position have been described in several patients with MYO7A-related disorders (PMIDs: 16963483, 9382091, 27460420). This sequence change is absent from the large population databases such as ExAC and gnomAD. This sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -

May 29, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val1501Glyfs*2) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 16963483). This variant is also known as 4501_4502delGT. ClinVar contains an entry for this variant (Variation ID: 550495). For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 1 Pathogenic:2

Mar 25, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 26, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555099541; hg19: chr11-76909597;