ClinVar Miner

Submissions for variant NM_138691.2(TMC1):c.1763+3A>G (rs370898981)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000293958 SCV000330030 pathogenic not provided 2018-04-17 criteria provided, single submitter clinical testing The c.1763+3A>G variant in the TMC1 gene has been reported previously in the homozygous state in several siblings with post-lingual, nonsyndromic, progressive sensorineural hearing loss (de Heer et al., 2011). The variant was also reported in the compound heterozygous state, opposite of a second TMC1 nonsense variant, in siblings with prelingual, moderate to profound, nonsyndromic hearing loss (Schrauwen et al., 2013). The c.1763+3A>G variant reduces the quality of the splice donor site in intron 19, and is expected to cause abnormal gene splicing. PCR results of patient-derived c.1763A>G RNAs showed the normal splicing signal was completely abolished when compared to normal control RNA (de Heer et al., 2011). The aberrant splicing results in a 47 base pair extension of exon 19, causing a frameshift, leading to a premature stop codon in exon 20 and the incorporation of 81 aberrant amino acids in the protein (de Heer et al., 2011). The c.1763+3A>G variant is observed in 30/25792 (0.12%) alleles from individuals of Finnish background and 163/277034 total alleles, in large population cohorts (Lek et al., 2016).] We interpret c.1763+3A>G as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000357976 SCV000480643 likely benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000760983 SCV000480644 likely pathogenic Deafness, autosomal recessive 7 2017-04-28 criteria provided, single submitter clinical testing The TMC1 c.1763+3A>G splice region variant was first reported by de Heer et al. (2011) in a homozygous state in three siblings from a large, distantly-consanguineous Dutch family affected with autosomal recessive nonsyndromic hearing loss. Both unaffected parents were heterozygous for this variant. The c.1763+3A>G variant was subsequently identified in a compound heterozygous state with a nonsense variant in a patient of European ethnicity (Schrauwen et al. 2013). The variant was found in a heterozygous state in one of 177 Dutch control individuals and is reported at a frequency of 0.00130 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR analysis on RNA isolated from blood of a homozygous patient revealed that the c.1763+3A>G variant causes alternative splicing and introduces 47 bp of intronic sequence into exon 19, which ultimately results in a frameshift and premature stop. Minigene analysis revealed that the variant completely abolished the normal splicing signal (de Heer et al. 2011). Based on the evidence, the p.1763+3A>G variant is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041134 SCV000064825 pathogenic Rare genetic deafness 2017-04-11 criteria provided, single submitter clinical testing The c.1763+3A>G variant in TMC1 has been previously reported in the homozygous s tate in one individual and in the compound heterozygous state in five other indi viduals with hearing loss, and segregated in five affected family members (de He er 2011, Schrauwen 2013, LMM data). It has been identified in 0.1% (153/152370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs370898981). This variant is located in the 5' spli ce region, and RT-PCR analysis of RNA from affected individuals reveals abnormal splicing of TMC1 transcripts resulting in a premature stop codon (de Heer 2011) . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive nonsyndromic sensorineural hearing loss. ACMG/AMP Criteria appl ied: PM3_VeryStrong, PP1_Strong, PS3.
Molecular Diagnostics Laboratory,M Health: University of Minnesota RCV000760983 SCV000890894 pathogenic Deafness, autosomal recessive 7 2017-06-21 criteria provided, single submitter clinical testing

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