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

gnomAD frequency: 0.00019  dbSNP: rs142746163

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793360	SCV000932708	pathogenic	not provided	2024-10-28	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs142746163, gnomAD 0.6%), 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: 27610647). ClinVar contains an entry for this variant (Variation ID: 228748). For these reasons, this variant has been classified as Pathogenic.
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	2024-09-09	criteria provided, single submitter	clinical testing	Reported in a patient with hearing loss in published literature; clinical information is limited (PMID: 27610647); 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: 31345219, 31980526, 37435641, 27610647)
Revvity Omics, Revvity	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001782705	SCV005202636	pathogenic	Autosomal recessive nonsyndromic hearing loss 42	2024-07-11	criteria provided, single submitter	clinical testing	Variant summary: ILDR1 c.772C>T (p.Gln258X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0005 in 137142 control chromosomes, predominantly at a frequency of 0.006 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ILDR1 causing Autosomal Recessive Nonsyndromic Hearing Loss 42 phenotype. However, c.772C>T has been reported in the literature in individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 42 (e.g. Chen_2016). These data indicate that the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27610647). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 228748). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001782705	SCV005417805	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 42		criteria provided, single submitter	clinical testing	PVS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001782705	SCV006054470	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 42	2020-08-13	criteria provided, single submitter	research