ClinVar Miner

Submissions for variant NM_000441.1(SLC26A4):c.554G>C (p.Arg185Thr) (rs542620119)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169232 SCV000220501 likely pathogenic Pendred syndrome 2014-07-10 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000778810 SCV000915190 likely pathogenic SLC26A4-Related Disorders 2018-08-15 criteria provided, single submitter clinical testing The SLC26A4 c.554G>C (p.Arg185Thr) variant is a missense variant that has been reported in a total of three individuals with nonsyndromic hearing loss or Pendred syndrome, including in a compound heterozygous state in one and in a heterozygous state in two (Pourova et al. 2010; Cirello et al. 2012; Chattaraj et al. 2013). One of the heterozygotes was also heterozygous for a missense variant in the FOXI1 gene, which is said to display digenic inheritance with SLC26A4. The p.Arg185Thr variant is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells, HEK293 phoenix cells and Xenopus oocytes have demonstrated the variant results in a trafficking defect, altered maturation, and reduced function compared to wildtype. Based on the collective evidence, the p.Arg185Thr variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000214962 SCV000271454 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2016-01-04 criteria provided, single submitter clinical testing The p.Arg185Thr variant in SLC26A4 has been previously reported in three individuals with hearing loss and enlarged vestibular aqueducts, including one individual who was compound heterozygous for a second pathogenic variant in the SLC26A4 gene (Chattaraj 2013, Cirello 2012, Pourova 2010). This variant has been identified in 12/66734 (0.02%) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs542620119); however, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies reveal that the variant results in abnormal cellular localization of the protein and significant reduction in its normal functional activity (Cirello 2012, Chattaraj 2013), supporting a deleterious effect for this variant. In addition, computational tools and conservation analyses predict that the p.Arg185Thr variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic.
SIB Swiss Institute of Bioinformatics RCV000677335 SCV000803604 uncertain significance Enlarged vestibular aqueduct 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for DFNB4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:22285650). PM2-Supporting => PM2 downgraded in strength to Supporting. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:24051746).

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