ClinVar Miner

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

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Total submissions: 19
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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.
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 Deafness, autosomal recessive 4, with 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 Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000414330 SCV000932353 pathogenic not provided 2020-10-19 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 this variant induces altered splicing and may result 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. Studies have shown that this variant is associated with exon 8 skipping, which introduces a frameshift (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 2019-12-20 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.919-2A>G is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18641518. Classification of NM_000441.1(SLC26A4):c.919-2A>G is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000005112 SCV001244771 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-10-27 criteria provided, single submitter clinical testing A heterozygous canonical splice-site variant, NM_000441.1(SLC26A4): c.919-2A>G, has been identified in intron 7 of the SLC26A4 gene. This substitution is predicted to cause aberrant splicing and loss of protein function either by truncation involving more than half the protein by or nonsense-mediated decay. The nucleotide at this position has very high conservation (100 vertebrates, UCSC) and in silico software predicts that the acceptor site of intron 7 will be altered. This variant is present in the gnomAD database with a global frequency of 0.034% (93 in 276808, 0 homozygotes) and in East Asian populations at a frequency of 0.48% (91 in 18860, 0 homozygotes). This commonly observed variant has been previously described as pathogenic in multiple families with severe to profound hearing loss (ClinVar, ClinVar, Li, Q. et al. (2012), Lee, HJ. et al. (2014),Mori, K.et al. (2016), Wang, Q-J. et al. (2007),Jung, J. et al. (2017)). Based on current information this variant has been classified as PATHOGENIC.The presence of these two variants in trans (observed in IGV) confirms compound heterozygous inheritance consistent with autosomal recessive deafness.
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.
OMIM RCV000005112 SCV000025288 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2009-05-01 no assertion criteria provided literature only
GeneReviews RCV000005112 SCV000086787 pathologic Deafness, autosomal recessive 4, with 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 Deafness, autosomal recessive 4, with 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 Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 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 Autosomal recessive nonsyndromic deafness no assertion criteria provided research

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