ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.919-2A>G (rs111033313)

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Total submissions: 14
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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, Partners HealthCare 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.
Counsyl RCV000169120 SCV000220324 pathogenic Pendred syndrome 2014-05-16 criteria provided, single submitter literature only
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 2017-12-30 criteria provided, single submitter clinical testing The c.919-2 A>G pathogenic variant has been reported multiple times in association with varying degrees of hearing loss (Lee et al., 2014, Wang et al., 2007). Lee et al. (2014) utilized functional studies to determine that this variant decreases the production of pendrin and predicted, through in silico analysis, that this reduction was due to c.919-2 A>G compromising the splice acceptor site in intron 7. Therefore, we interpret this variant as pathogenic.
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000005112 SCV000611827 pathogenic Enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414330 SCV000700798 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036513 SCV000893726 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000414330 SCV000932353 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the SLC26A4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs111033313, ExAC 0.4%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with Pendred syndrome in several families as homozygous or as compound heterozygous (PMID: 10874637, 11502831) and has been reported in multiple individuals with non-syndromic hearing loss in East Asia (PMID: 11502831, 16711435, 23958391,24007330). ClinVar contains an entry for this variant (Variation ID: 4840). This variant is also known as IVS8-2A>G and 1143-2A>G in the literature. Experimental studies have shown that this intronic change decreases the production of pendrin (PMID: 24007330) and results in loss of exon 8 (PMID: 15574297). In addition, a mouse knock-in model with this variant for hearing loss was found to recapitulate the human phenotype (PMID: 21811566). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169120 SCV001163092 pathogenic Pendred syndrome criteria provided, single submitter clinical testing
OMIM RCV000005112 SCV000025288 pathogenic Enlarged vestibular aqueduct 2009-05-01 no assertion criteria provided literature only
GeneReviews RCV000005112 SCV000086787 pathologic Enlarged vestibular aqueduct 2011-12-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000005112 SCV000902365 pathogenic Enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV000005112 SCV000994911 affects Enlarged vestibular aqueduct 2019-08-20 no assertion criteria provided clinical testing in vitro experiment

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