ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.-3-2A>G (rs397516411)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824761 SCV000060070 pathogenic Rare genetic deafness 2018-06-04 criteria provided, single submitter clinical testing The c.-3-2A>G variant in SLC26A4 has been identified in 11 compound heterozygous individuals and 1 homozygous individual with hearing loss and clinical features of DFNB4-related hearing loss/Pendred syndrome (EVA or temporal bone abnormalit ies and one with a goiter) (Lopez-Bigas 2001, Pryor 2005, Albert 2006, Choi 2009 a, Choi 2009b, Soh 2015, DeLuca 2015, LMM data). This variant has also been iden tified in 21/88534 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org). Although this variant has been seen in th e general population, its frequency is low enough to be consistent with a recess ive 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 criteria to be classified as pathogenic for DFNB4-related hearing loss/Pendred syndrome in an autosomal recessive manner based upon presence in affected individuals and predi cted impact on protein. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS4, PM 2_Supporting
Fulgent Genetics,Fulgent Genetics RCV000036415 SCV000894401 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000665503 SCV001193899 likely pathogenic Pendred syndrome 2020-01-03 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.-3-2A>G is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID: 25394566, 21704276, 23965030 and 16570074. Classification of NM_000441.1(SLC26A4):c.-3-2A>G is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV001063867 SCV001228731 likely pathogenic not provided 2020-10-20 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs397516411, ExAC 0.06%). This variant has been observed in several individuals affected with SLC26A4-related conditions (PMID: 16570074, 25394566, 26022370). ClinVar contains an entry for this variant (Variation ID: 43486). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV001063867 SCV001787543 pathogenic not provided 2021-06-16 no assertion criteria provided clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26022370, 25394566, 16570074, 31980526, 14679580, 15689455, 23965030, 21704276, 25525159, 19204907)

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