Submissions for variant NC_000007.14:g.107660756T>C

gnomAD frequency: 0.00209  dbSNP: rs60284988

Total submissions: 13

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	2024-01-17	reviewed by expert panel	curation	The c.-103T>C (NM_000441.2) variant is a substitution in the 5’ UTR of SLC26A4. Because the variant is located in the 5’ UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v4.0.0 is 0.3% (262/68066 alleles) in the European (non-Finnish) population, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). This variant has been detected in 2 individuals with hearing loss and additional features of Pendred syndrome (enlarged vestibular aqueducts (EVA) and Mondini dysplasia) who were compound heterozygous for the variant and a pathogenic variant with phase confirmed in trans in one individual (PMID: 19204907, 25991456). It has also been identified in two additional compound heterozygous individuals with hearing loss, one with a likely pathogenic and one with a variant of uncertain significance, though phase was not confirmed in either individual (SCV000491274.5). However, due to the allele frequency meeting BS1 criteria, PP4 and PM3 were not applied. There have been many reported heterozygous observations in individuals with EVA/Pendred syndrome (PMID:17503324, 23208854, 23965030, 25991456). Functional studies imply that the variant occurs in a binding site that is a major transcriptional regulatory element of SLC26A4 and is necessary for FOXI1-induced transcriptional activation of SLC26A4 (PMID:25910213, 17503324; PS3_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1, PS3_P (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024).
Laboratory for Molecular Medicine, Mass General Brigham 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 (http://gnomad.broadinstitute.org). 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 Laboratory Services, Illumina	RCV004528080	SCV000466073	uncertain significance	SLC26A4-related disorder	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	uncertain significance	not provided	2024-09-27	criteria provided, single submitter	clinical testing	Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000927013.1; PMID: 30311386); This variant is associated with the following publications: (PMID: 25910213, 19787632, 24860705, 22285650, 23208854, 18322141, 23555729, 21045265, 30068397, 29196752, 31633822, 28780564, 25960948, 34426522, 25991456, 23965030, 17503324, 19204907)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412985	SCV001733069	benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000005109	SCV002060309	uncertain significance	Pendred syndrome	2021-10-01	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.-103T>C is a 5' non-coding variant classified as a variant of uncertain significance in the context of Pendred syndrome. c.-103T>C has been observed in cases with relevant disease (PMID: 17503324, 19204907, 23208854, 23555729, 23965030, 25991456, 31633822, 30068397). Functional assessments of this variant are available in the literature (PMID: 17503324). c.-103T>C has been observed in population frequency databases (gnomAD: NFE 0.34%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.-103T>C as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000412985	SCV005330041	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SLC26A4: BS1, BS2
OMIM	RCV000005109	SCV000025285	pathogenic	Pendred syndrome	2007-06-01	no assertion criteria provided	literature only
OMIM	RCV000005110	SCV000025286	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412985	SCV001953564	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000412985	SCV001970662	uncertain significance	not provided		no assertion criteria provided	clinical testing