ClinVar Miner

Submissions for variant NM_001199799.2(ILDR1):c.772C>T (p.Gln258Ter)

gnomAD frequency: 0.00019  dbSNP: rs142746163
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000217496 SCV000271847 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing The p.Gln258X variant in ILDR1 (NM_001199799.1) has now been identified by our l aboratory in two individuals with hearing loss, one of whom had an alternate gen etic cause of their hearing loss identified. This variant has also been identifi ed in 1/206 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142746163). Although this variant has b een seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 258 in exon 6 of the ILDR1 NM_001199799.1 transcript isoform. Howev er, in an alternate isoform of ILDR1 (NM_175924.3), the variant occurs in an int ronic region (c.647-218C>T in intron 5) and is not predicted to have an impact o n that protein isoform. While loss of function variants in ILDR1 have been shown to cause hearing loss, none have been reported in exon 6 of the NM_001199799.1 ILDR1 transcript to date. Therefore, it is unclear whether loss of function vari ants in exon 6 of this transcript isoform can lead to hearing loss, or only thos e affecting coding regions of the NM_175924.3 transcript isoform are causative f or disease. In summary, the clinical significance of the p.Gln258X variant in th e NM_001199799.1 transcript of ILDR1 is uncertain.
Invitae RCV000793360 SCV000932708 pathogenic not provided 2023-09-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228748). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 27610647). This variant is present in population databases (rs142746163, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Gln258*) in the ILDR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ILDR1 are known to be pathogenic (PMID: 21255762).
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375435 SCV001572012 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PVS1_Strong, PM2_Supporting
GeneDx RCV000793360 SCV001802463 uncertain significance not provided 2021-03-24 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: 31980526, 27610647)
Revvity Omics, Revvity Omics RCV001782705 SCV002016709 likely pathogenic Autosomal recessive nonsyndromic hearing loss 42 2020-09-01 criteria provided, single submitter clinical testing
3billion RCV001782705 SCV002058780 pathogenic Autosomal recessive nonsyndromic hearing loss 42 2022-01-03 criteria provided, single submitter clinical testing 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 (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000469, PM2_M). The variant has been reported to be associated with ILDR1 related disorder (ClinVar ID: VCV000228748, PMID:27610647, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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