chr11-77192243-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000260.4(MYO7A):c.4117C>T(p.Arg1373*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,896 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000260.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- nonsyndromic genetic hearing lossInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- autosomal recessive nonsyndromic hearing loss 2Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
- Usher syndrome type 1Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
- Usher syndrome type 1BInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- autosomal dominant nonsyndromic hearing loss 11Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- autosomal dominant nonsyndromic hearing lossInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Usher syndrome type 2Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYO7A | ENST00000409709.9 | c.4117C>T | p.Arg1373* | stop_gained | Exon 31 of 49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.4117C>T | p.Arg1373* | stop_gained | Exon 31 of 49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.4084C>T | p.Arg1362* | stop_gained | Exon 32 of 50 | 1 | ENSP00000386635.2 | |||
MYO7A | ENST00000458169.2 | c.1660C>T | p.Arg554* | stop_gained | Exon 11 of 29 | 1 | ENSP00000417017.2 | |||
MYO7A | ENST00000670577.1 | n.1957C>T | non_coding_transcript_exon_variant | Exon 14 of 32 | ENSP00000499323.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 249226 AF XY: 0.00000740 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727124 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate defects in electrophysiology, morphology, and pluripotency in p.(R1373*) cell lines that were resolved to levels close to controls by genetic correction of p.(R1373*) (Tang et al., 2016); This variant is associated with the following publications: (PMID: 21436283, 31589614, 33576163, 27013738, 16470552) -
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This sequence change creates a premature translational stop signal (p.Arg1373*) 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 present in population databases (rs766641715, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 16470552, 21436283). ClinVar contains an entry for this variant (Variation ID: 551138). For these reasons, this variant has been classified as Pathogenic. -
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Usher syndrome type 1 Pathogenic:2
The observed stop gained c.4117C>T(p.Arg1373Ter) variant in MYO7A gene has been reported previously in compound heterozygous state in multiple individuals affected with Usher syndrome (Roux AF, et al., 2011; Jaijo T, et al., 2006; HURPADE, S., et al.). The c.4117C>T variant has been reported with allele frequency of 0.001% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.4117C>T in MYO7A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg1373Ter) in the MYO7A gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in MYO7A gene have been previously reported to be disease causing (Weston MD, et al., 1996). For these reasons, this variant has been classified as Pathogenic. The same variant in MYO7A gene has been identified in heterozygous state in sibling This variant is absent in paternal cousin [Mrs. SHITAL RAM GIRAM, id: 30607400182]. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000551138 /PMID: 16470552). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Usher syndrome Pathogenic:1
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Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Usher syndrome type 1B Pathogenic:1
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Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at