ClinVar Miner

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

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Total submissions: 10
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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 either hearing loss or hearing loss with enlarged vestibular aqueducts (EVA; Yang 2007, Yang 2009, Choi 2009, Landa 2013, Schrauwen 2013, Tang 2015, Baux 2017, Carvalho 2018, LMM data). However, only 2 of these individuals harbored a second pathogenic variant in SLC26A4, including one individual with hearing loss and EVA who carried a pathogenic p.Leu236Pro variant in trans (Choi 2009) and one individual with hearing loss and Mondini malformation who carried a pathogenic p.Thr416Pro variant (phasing not reported; Tang 2015). Furthermore, at least 3 probands had alternate genetic etiologies for their hearing loss (LMM data, Baux 2017). This variant has also been identified in 0.34% (52/15424; 0.26% using the lower threshold of 95% confidence interval) of European chromosomes by gnomAD ( This frequency is higher than expected for pathogenic variation in SLC26A4. Finally, the c.-103T>C variant falls within the 5' untranslated region (UTR) of the SLC26A4 gene, and functional studies have produced conflicting results regarding its impact on protein expression or function (Alder 2008 vs Yang 2007, Yang 2009). In summary, due to the conflicting functional evidence, the lack of biallelic affected individuals, and a similar frequency amongst cases (0.3%, 23/6678 chromosomes) and the general population (0.3% European chromosomes in gnomAD), the clinical significance of the c.-103T>C variant is uncertain. 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
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375210 SCV001571912 pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Supporting, BP4_Supporting
Invitae RCV000412985 SCV001733069 benign not provided 2020-12-08 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 Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2007-06-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000412985 SCV001553599 uncertain significance not provided no assertion criteria provided clinical testing The SLC26A4 c.103T>C variant was identified as a heterozygous variant in 14 of 674 individuals (frequency: 0.01) with autosomal recessive Pendred syndrome or nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA); a second pathogenic variant was only identified in 3 of these cases (Carvalho_2018_PMID:30068397, Yang_2007_PMID:17503324, Choi_2009_PMID:19204907, Tang_2015_PMID:2599145). Functional analysis shows that this variant diminishes FOXI1 transactivation of SLC26A4 compared to wildtype (Yang_2007_PMID:17503324). The variant was identified in dbSNP (ID: rs60284988), LOVD 3.0 and ClinVar (classified as uncertain significance by the ClinGen Hearing Loss Variant Curation Expert Panel, Counsyl, Laboratory for Molecular Medicine and Illumina, and as likely pathogenic by GeneDx). The variant was identified in control databases in 66 of 31390 chromosomes at a frequency of 0.002103 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 6 of 1086 chromosomes (freq: 0.005525), Ashkenazi Jewish in 1 of 290 chromosomes (freq: 0.003448), European (non-Finnish) in 52 of 15424 chromosomes (freq: 0.003371), European (Finnish) in 4 of 3476 chromosomes (freq: 0.001151) and African in 3 of 8708 chromosomes (freq: 0.000345), but was not observed in the Latino, East Asian, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this timet. This variant is classified as a variant of uncertain significance.

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