rs876657656

Variant names:

• chr11-17574878-T-TAACTGGACACCC
• rs876657656
• NM_001292063.2:c.2453_2454insACTGGACACCCA

Variant summary

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

The NM_001292063.2(OTOG):​c.2453_2454insACTGGACACCCA​(p.Tyr818delinsTerLeuAspThrHis) variant causes a stop gained, disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000111 in 1,537,294 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: OTOG NM_001292063.2 stop_gained, disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.58

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

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 11-17574878-T-TAACTGGACACCC is Pathogenic according to our data. Variant chr11-17574878-T-TAACTGGACACCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228283.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
OTOG	NM_001292063.2	c.2453_2454insACTGGACACCCA	p.Tyr818delinsTerLeuAspThrHis	stop_gained, disruptive_inframe_insertion	Exon 20 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2489_2490insACTGGACACCCA	p.Tyr830delinsTerLeuAspThrHis	stop_gained, disruptive_inframe_insertion	Exon 19 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.2453_2454insACTGGACACCCA	p.Tyr818delinsTerLeuAspThrHis	stop_gained, disruptive_inframe_insertion	Exon 20 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.2489_2490insACTGGACACCCA	p.Tyr830delinsTerLeuAspThrHis	stop_gained, disruptive_inframe_insertion	Exon 19 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000810 AC: 11 AN: 135794 Hom.: 0 AF XY: 0.0000552 AC XY: 4 AN XY: 72480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000256

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1385094 Hom.: 0 Cov.: 32 AF XY: 0.00000733 AC XY: 5 AN XY: 681774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000431

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 AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 25, 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.Tyr830*) in the OTOG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (no rsID available, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 228283). For these reasons, this variant has been classified as Pathogenic. -

Apr 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive nonsyndromic hearing loss 18B Pathogenic:1

Feb 06, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). 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: VCV000228283). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Rare genetic deafness Pathogenic:1

Jan 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr830X variant in OTOG has been previously reported by our laboratory in the homozygous state in one individual with mild to moderate hearing loss. This variant has not been identified in large population studies, though the ability of these studies to accurately detect insertions or deletions may be limited. T his variant creates a premature termination codon at position 830, which is pred icted to lead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schraders 2012), and disruption of Otog in mice resulted in deafness supportin g of a loss-of-function mechanism for the disease (Simmler 2000). In summary, al though additional evidence is required to strengthen the gene-disease associatio n for OTOG and hearing loss, the p.Tyr830 variant is likely pathogenic based on its predicted impact on the protein and our currently knowledge of the gene. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657656; hg19: chr11-17596425;