ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1588T>C (p.Tyr530His) (rs111033254)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036449 SCV000060104 pathogenic Rare genetic deafness 2015-01-26 criteria provided, single submitter clinical testing The p.Tyr530His variant in SLC26A4 has been reported in at least 20 individuals with hearing loss with EVA and/or Mondini dysplasia or with Pendred syndrome (Al bert 2006, Banghova 2008, Blons 2004, Borck 2003, Campbell 2001, Choi 2009, Coyl e 1998, Prasad 2004, Pryor 2005, LMM unpublished data). The variant was compound heterozygous in at least 14 of those probands. This variant was present in 1/6 6632 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs111033254). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a r ecessive carrier frequency. One study has shown that the Tyr530His variant impa cts protein function (Choi 2009). In summary, this variant meets our criteria to be classified as pathogenic (http://personalizedmedicine.partners.org/).
Counsyl RCV000005107 SCV000221064 likely pathogenic Pendred syndrome 2015-01-21 criteria provided, single submitter literature only
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000005107 SCV000538064 pathogenic Pendred syndrome 2016-01-27 criteria provided, single submitter clinical testing The c.1588T>C (p.Tyr530His) missense variant in the SLC26A4 gene has been reported as a common deleterious variant associated with Pendred Syndrome (Coyle et al., 1998; Blons et al., 2004). This variant has been reported in several affected individuals, often in trans with a second deleterious variant (V138F, T410M, c.2089+1G>A, V422D, T416P, Y78C, F355S) (Blons et al., 2004; Banghova et al., 2008; Borck et al., 2009; Ladsous et al., 2014). Functional studies have shown this variant affects protein localization within the cell; additionally, some affected individuals harboring this variant have elevated thyroglobulin (Choi et al., 2009; Ladsous et al., 2014). This variant is reported at low frequency within the control population databases (Exome Sequencing Project [ESP] = NA; 1000 Genomes = NA; and ExAC = 0.002). Multiple in silico algorithms predict the variant to have a deleterious effect (GERP = 5.96; CADD = 26.2; PolyPhen = 1; SIFT = 0.02). In addition, reputable diagnostic laboratories have reported this variant as Pathogenic.Therefore, this collective evidence supports the classification of the c.1588T>C (p.Tyr530His) as an autosomal recessive Pathogenic variant for Pendred Syndrome/ Non-syndromic Hearing Loss DFNB4.
Invitae RCV001229712 SCV001402166 pathogenic not provided 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 530 of the SLC26A4 protein (p.Tyr530His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs111033254, ExAC 0.002%). This variant has been observed in individual(s) with Pendred syndrome (PMID: 9618167, 12788906, 19204907, 24224479, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4836). This variant has been reported to affect SLC26A4 protein function (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005107 SCV000025283 pathogenic Pendred syndrome 2009-04-01 no assertion criteria provided literature only
Natera, Inc. RCV000005107 SCV001459929 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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