ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.919-2A>G

gnomAD frequency: 0.00018  dbSNP: rs111033313
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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000169120 SCV000840527 pathogenic Pendred syndrome 2018-09-20 reviewed by expert panel curation The filtering allele frequency of the c.919-2A>G variant in the SLC26A4 gene is 0.4% for East Asian chromosomes in the Genome Aggregation Database (91/18860 with 95% CI) , which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, the c.919-2A>G variant in SLC26A4 is predicted to cause the skipping of a biologically-relevant out-of-frame exon 8. This is then expected to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). Additionally, this variant has been detected in 16 patients with hearing loss in trans with more than 4 pathogenic variants (PM3_VeryStrong; PMID: 23151025). The c.919-2A>G variant in SLC26A4 has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; 10874637). Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PP1_Strong, PM3_VeryStrong, BS1.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000824767 SCV000060168 pathogenic Rare genetic deafness 2011-02-01 criteria provided, single submitter clinical testing The 919-2A>G variant in SLC26A4 has been reported in over 400 individuals with n onsyndromic hearing loss or Pendred syndrome (Coucke 1999, Yong 2001, Park 2003, Tsukamoto 2003, Park 2005, Dai 2008). This variant was found to segregate with Pendred syndrome in two large families (Coucke 1999, Iwasaki 2006). In addition, is predicted to cause abnormal splicing because the nucleotide substitution occ urs in the invariant region of the splice consensus sequence. In summary, this v ariant meets our criteria to be classified as pathogenic.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000169120 SCV000267507 likely pathogenic Pendred syndrome 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000414330 SCV000490809 pathogenic not provided 2022-02-22 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect; variant results in skipping of exon 8 and a new stop codon at position 348 (Lu et al., 2014); This variant is associated with the following publications: (PMID: 16711435, 20842945, 19786220, 23469187, 21811566, 25525159, 26100058, 20301640, 28505178, 28786104, 27308839, 28640090, 29106878, 28901477, 31442870, 30282152, 30589569, 30693673, 29234782, 31347505, 31035178, 30473558, 30036422, 31107121, 30268946, 29681450, 30554688, 31599023, 31980526, 32203226, 30896630, 32425884, 24338212, 15574297, 11502831, 21961810, 23151025, 27176802, 27498126, 24007330, 10874637, 28925492, 28981942, 28093008, 28964290, 30086623, 31415960, 30970410, 30898719, 30762457, 29921047, 29634755, 27729126, 27240500, 30733538, 30842343, 31692010, 31564438, 32574949, 29650690, 31914302, 31541171, 31827275, 30275481, 31656273, 15905611, 34426522, 32877901, 34170635, 33614372, 32447495, 33724713, 32645618, 33597575, 33638616, 25231367, 17718863, 30311386, 15679828, 14508505, 23958391)
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000005112 SCV000611827 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2017-07-01 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000414330 SCV000700798 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036513 SCV000893726 pathogenic Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000414330 SCV000932353 pathogenic not provided 2021-12-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the SLC26A4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs111033313, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with Pendred syndrome or non-syndromic hearing loss (PMID: 10874637, 11502831). It is commonly reported in individuals of East Asian ancestry (PMID: 11502831, 16711435, 23958391, 24007330). This variant is also known as IVS8-2A>G and 1143-2A>G. ClinVar contains an entry for this variant (Variation ID: 4840). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 15574297). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169120 SCV001163092 pathogenic Pendred syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000169120 SCV001194114 pathogenic Pendred syndrome 2021-11-08 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.919-2A>G is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.919-2A>G has been observed in cases with relevant disease (PMID: 18641518). Functional assessments of this variant are not available in the literature. c.919-2A>G has been observed in population frequency databases (gnomAD: EAS 0.49%). In summary, NM_000441.1(SLC26A4):c.919-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. ​
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000169120 SCV001244771 pathogenic Pendred syndrome 2022-06-24 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA analysis using patient cells showed an out-of-frame skipping of exon 8 which resulted in a frameshift and a premature termination codon, and subsequent nonsense-mediated decay of the resulting protein (PMID: 15574297). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 103 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with non-syndromic enlarged vestibular aqueduct and Pendred syndrome (ClinVar, PMID: 25372295). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169120 SCV001572510 pathogenic Pendred syndrome 2021-04-08 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.919-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 8 although low levels of normal transcript were also reported in tissues from patients homozygous for this variant (example Lee_2014). The variant allele was found at a frequency of 0.00036 in 251010 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00036 vs 0.0035), allowing no conclusion about variant significance. c.919-2A>G has been widely reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coucke_1999, Li_2012). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000005112 SCV002059131 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2022-01-03 criteria provided, single submitter clinical testing The variant was co-segregated with Deafness, autosomal recessive 4 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 10874637) (PP1_S). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000004840, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000365, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 23151025, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000005112 SCV000025288 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2009-05-01 no assertion criteria provided literature only
GeneReviews RCV000169120 SCV000086787 pathogenic Pendred syndrome 2017-10-19 no assertion criteria provided literature only
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000005112 SCV000902365 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2019-02-26 no assertion criteria provided case-control
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV000005112 SCV000994911 affects Autosomal recessive nonsyndromic hearing loss 4 2019-08-20 no assertion criteria provided clinical testing in vitro experiment
The Core Laboratory in Medical Center of Clinical Research,Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine RCV000169120 SCV001438732 pathogenic Pendred syndrome 2020-05-12 no assertion criteria provided clinical testing
Natera, Inc. RCV000169120 SCV001455804 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV001291247 SCV001479672 likely pathogenic Hearing loss, autosomal recessive no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000414330 SCV001958199 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000414330 SCV001973484 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000414330 SCV002020689 pathogenic not provided 2020-03-25 no assertion criteria provided clinical testing

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