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

gnomAD frequency: 0.00056  dbSNP: rs370898981

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
GeneDx	RCV000293958	SCV000330030	pathogenic	not provided	2022-06-27	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss-of-function; 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); This variant is associated with the following publications: (PMID: 31980526, 33352559, 24933710, 34758253, 23208854, 21252500, 31152317)
Illumina Laboratory Services, Illumina	RCV000760983	SCV000480644	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000760983	SCV000890894	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2017-06-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000293958	SCV002018979	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000293958	SCV003300394	pathogenic	not provided	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the TMC1 gene. It does not directly change the encoded amino acid sequence of the TMC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs370898981, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 21252500). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 47864). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site resulting in the addition of 47 nucleotides from the intron and a subsequent frameshift, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21252500). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782031	SCV005394003	pathogenic	Nonsyndromic genetic hearing loss	2024-09-04	criteria provided, single submitter	clinical testing	Variant summary: TMC1 c.1763+3A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (de Heer_2011). The variant allele was found at a frequency of 0.00061 in 251290 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TMC1 causing Nonsyndromic Hearing Loss And Deafness, Type 7 (0.00061 vs 0.0011), allowing no conclusion about variant significance. c.1763+3A>G has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 7 and this variant co-segregated with the disease (de Heer_2011, Kraatari-Tiri_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35407445, 21252500). ClinVar contains an entry for this variant (Variation ID: 47864). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042116	SCV005679368	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 7; Autosomal dominant nonsyndromic hearing loss 36	2024-05-06	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542674	SCV001760241	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 36		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000293958	SCV001956099	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000293958	SCV001969920	pathogenic	not provided		no assertion criteria provided	clinical testing