ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1614+1G>A (rs111033312)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036451 SCV000060106 pathogenic Rare genetic deafness 2015-07-09 criteria provided, single submitter clinical testing The c.1614+1G>A variant in SLC26A4 has been reported in 13 individuals with hear ing loss or Pendred syndrome, and 8 of them were compound heterozygous (Fugazzol a 2002, Blons 2004, Pera 2008, Pourova 2010, LMM unpublished data). This variant has also been identified in 3/66512 European chromosomes by the Exome Aggregati on Consortium (ExAC,; dbSNP rs111033312). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic.
GeneDx RCV000359760 SCV000329897 pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The c.1614+1G>A pathogenic variant in the SLC26A4 gene has been reported previously in a female patient with goiter, positive perchlorate test, subclinical hypothyroidism, enlargement of the vestibular aqueduct, and severe sensorineural hearing loss (Fugazzola et al., 2002). Although a second c.1197delT variant was reported, parental segregation studies were not performed to determine if these two reported SLC26A4 variants were present in cis or trans. This splice site variant destroys the canonical splice donor site in intron 14. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1614+1G>A variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1614+1G>A as a pathogenic variant.
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000515698 SCV000611817 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
Invitae RCV000359760 SCV001230542 pathogenic not provided 2020-10-07 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 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 (rs111033312, ExAC 0.005%). This variant has been observed in several individuals affected with nonsyndromic enlarged vestibular aqueduct and hearing loss (PMID: 11919333, 20128824, 15355436, 20597900, 24105851). ClinVar contains an entry for this variant (Variation ID: 43516). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000515698 SCV000902375 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control
Counsyl RCV000984218 SCV001132292 pathogenic Pendred syndrome 2015-10-20 no assertion criteria provided clinical testing
Natera, Inc. RCV000984218 SCV001459930 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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