Submissions for variant NM_001039141.3(TRIOBP):c.5014G>T (p.Gly1672Ter)

gnomAD frequency: 0.00054  dbSNP: rs200045032

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000601096	SCV000711222	uncertain significance	not specified	2018-12-19	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly1672X variant in exon 9 of TRIOBP has been reported in compound heterozygous state wit h frameshift variants in exon 7 (NM_001039141.2) in 2 individuals hearing loss ( Pollack 2017, Wesdorp 2017, Zazo-Seco 2017). This variant has also been identifi ed in 0.17% (17/10060) of Ashkenazi Jewish chromosomes and 0.08% (98/124714) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1672 which is predic ted to lead to a truncated or absent protein; however, there are several alterna tely spliced TRIOBP isoforms in humans. All pathogenic truncating variants in T RIOBP reported to date have been identified in exon 7, which is common in both t he TRIOBP-5 and TRIOBP-4 transcripts. The p.Gly1672X variant occurs in exon 9 of the TRIOBP-5 transcript. It is unknown at this time if truncating variants imp acting only the TRIOBP-5 transcript are causative for hearing loss. In summary, while there is some suspicion for a pathogenic role, the clinical significance o f the p.Gly1672X variant is uncertain. ACMG/AMP Criteria applied: PM3, BS1_Suppo rting.
GeneDx	RCV000760513	SCV000890404	pathogenic	not provided	2022-01-26	criteria provided, single submitter	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; This variant is associated with the following publications: (PMID: 29197352, 28089734, 34426522, 28000701)
Baylor Genetics	RCV001329528	SCV001520988	pathogenic	Autosomal recessive nonsyndromic hearing loss 28	2020-09-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375312	SCV001571934	likely benign	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Supporting, BP4_Supporting, BP5_Supporting
Invitae	RCV000760513	SCV003283273	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1672*) in the TRIOBP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIOBP are known to be pathogenic (PMID: 16385457, 16385458, 20510926). This variant is present in population databases (rs200045032, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with deafness (PMID: 28000701, 28089734, 29197352). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 504691). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000760513	SCV004225759	likely pathogenic	not provided	2022-03-09	criteria provided, single submitter	clinical testing	PP1, PM2_supporting, PM3, PVS1
CeGaT Center for Human Genetics Tuebingen	RCV000760513	SCV004699271	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TRIOBP: PVS1, PM2
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000760513	SCV001951800	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000760513	SCV001970328	pathogenic	not provided		no assertion criteria provided	clinical testing