ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.-103T>C (rs60284988)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000005109 SCV000927013 uncertain significance Pendred syndrome 2018-09-24 reviewed by expert panel curation The filtering allele frequency of the c.-103T>C variant in the SLC26A4 gene is 0.28% for European (Non-Finnish) chromosomes by the Genome Aggregation Database (53/14998 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected one patient with EVA in trans with p.Leu236Pro, pathogenic variant, as well as in two patients with EVA in which the variant in trans is benign (c.-66C>G) or the phase was not identified (p.Thr416Pro) (PM3; PMID:19204907, 30068397, 25991456). The variant has also been observed in 12 heterozygous cases in which a second variant was not identified (PMID: 17503324, 29196752, 25991456, 23208854). At least one patient with a variant in this gene displayed features of enlarged vestibular aqueduct (PP4; PMID: 19204907). Functional studies demonstrate that this variant may impact FOXI1-induced transcriptional activation of SLC26A4 (PS3_Supporting; PMID: 17503324, 25910213). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PM3, PP4, PS3_Supporting.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154443 SCV000204112 uncertain significance not specified 2019-02-26 criteria provided, single submitter clinical testing The c.-103T>C variant in SLC26A4 has been reported in >20 individuals with eithe r hearing loss or hearing loss with enlarged vestibular aqueducts (EVA; Yang 200 7, Yang 2009, Choi 2009, Landa 2013, Schrauwen 2013, Tang 2015, Baux 2017, Carva lho 2018, LMM data). However, only 2 of these individuals harbored a second path ogenic variant in SLC26A4, including one individual with hearing loss and EVA wh o carried a pathogenic p.Leu236Pro variant in trans (Choi 2009) and one individu al with hearing loss and Mondini malformation who carried a pathogenic p.Thr416P ro variant (phasing not reported; Tang 2015). Furthermore, at least 3 probands h ad alternate genetic etiologies for their hearing loss (LMM data, Baux 2017). Th is variant has also been identified in 0.34% (52/15424; 0.26% using the lower th reshold of 95% confidence interval) of European chromosomes by gnomAD (http://gn This frequency is higher than expected for pathogenic variation in SLC26A4. Finally, the c.-103T>C variant falls within the 5' untrans lated region (UTR) of the SLC26A4 gene, and functional studies have produced con flicting results regarding its impact on protein expression or function (Alder 2 008 vs Yang 2007, Yang 2009). In summary, due to the conflicting functional evid ence, the lack of biallelic affected individuals, and a similar frequency amongs t cases (0.3%, 23/6678 chromosomes) and the general population (0.3% European ch romosomes in gnomAD), the clinical significance of the c.-103T>C variant is unce rtain. ACMG/AMP criteria applied: BS1_Supporting, PM3, PP4, PS3_Supporting.
Illumina Clinical Services Laboratory,Illumina RCV000359003 SCV000466073 uncertain significance SLC26A4-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The SLC26A4 c.-103T>C 5' UTR variant has been reported in at least four studies in which it was found in a total of 14 individuals with clinical features of Pendred syndrome or isolated hearing loss/impairment or nonsyndromic enlarged vestibular aqueduct. Among these individuals, the variant was identified in a compound heterozygous state in one individual, in conjunction with a second missense variant in one individual (phase unknown), and in a heterozygous state in 12 individuals (Yang et al. 2007; Choi et al. 2009; Landa et al. 2013; Tang et al. 2015). Although SLC26A4-related disorders are inherited in an autosomal recessive manner, it is not uncommon to detect a single disease-causing variant in patients due to testing limitations and biological complexities. Frequency information for the c.-103T>C variant is not available from the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium; however, the variant was absent from 452 control chromosomes (Yang et al. 2007; Choi et al. 2009). A luciferase promotor-reporter expression assay showed the variant reduces FOXI1 binding affinity and abolishes FOXI1-mediated transcriptional activation of SLC26A4 (Yang et al. 2007). Evidence for this variant is limited, therefore, the c.-103T>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000412985 SCV000491274 likely pathogenic not provided 2016-04-26 criteria provided, single submitter clinical testing The c.-103 T>C variant in the SLC26A4 gene has been previously published in patients with Pendred syndrome and enlarged vestibular aqueduct (Choi et al., 2009; Pique et al., 2014; Cirello et al., 2012; Schrauwen et al., 2013; Yang et al., 2007). It occurs at a position within the FOXI1 binding site of the SLC26A4 gene that is conserved in mammals. This position is a major transcriptional regulatory element (Pique et al., 2014; Yang et al., 2007). The c.-103 T>C variant is not predicted to result in an alternative start site; however, functional studies have shown that it may abolish FOXI1-mediated transactivation (Yang et al., 2007; Cirello et al., 2012). In addition, one other regulatory variant (c.-843 A>G) in the SLC26A4 gene has been reported in the Human Gene Mutation Database in association with enlarged vestibular aqueduct (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Counsyl RCV000005109 SCV000800741 uncertain significance Pendred syndrome 2018-03-26 criteria provided, single submitter clinical testing
OMIM RCV000005109 SCV000025285 pathogenic Pendred syndrome 2007-06-01 no assertion criteria provided literature only
OMIM RCV000005110 SCV000025286 pathogenic Enlarged vestibular aqueduct 2007-06-01 no assertion criteria provided literature only

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