ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1001+1G>A (rs80338849)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824768 SCV000060073 pathogenic Rare genetic deafness 2017-04-13 criteria provided, single submitter clinical testing The c.1001+1G>A variant in SLC26A4 has been previously described in the literatu re in individuals with Pendred syndrome/DFNB4 with well-established pathogenicit y (Coyle 1998, Campbell 2001, Bogazzi 2000, Lopez-Bigas 2001, Fugazzola 2002, Ts ukamoto 2003, Bogazzi 2004, Pryor 2005, Madden 2007, Pera 2008, Pourova 2010). T his variant is present in 47/125744 European chromosomes by the Genome Aggregati on Database; however, this frequency is low enough to be consistent with a carri er frequency for recessive hearing loss or Pendred syndrome (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs80338849). This variant occurs in the invariant r egion (+/- 1,2) of the splice consensus sequence and is predicted to cause alter ed splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive DFNB4/Pend red syndrome based on the previously reported biallelic occurrences in affected individuals, association with specific clinical features, a low frequency in the general population, and predicted impact to the protein. ACMG/AMP criteria appl ied: PVS1, PS4.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239276 SCV000296920 pathogenic not provided 2015-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000239276 SCV000329519 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing The c.1001+1G>A pathogenic variant in the SLC26A4 gene has been reported previously in association with SLC26A4-related disorders when present in trans with another SLC26A4 pathogenic variant (Coyle et al., 1998; Pryor et al., 2005; Pourová et al., 2010). The c.1001+1G>A pathogenic variant was also reported in trans with the wild type allele in two related individuals in which one individual was reported as unaffected and the other was reported to have non-syndromic hearing loss (Pryor et al., 2005). This splice site variant destroys the canonical splice donor site in intron 8 and 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.1001+1G>A variant was not observed at any significant frequency in approximately 6,500 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.1001+1G>A as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000390780 SCV000466091 pathogenic SLC26A4-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The SLC26A4 c.1001+1G>A variant is a well-known splice donor variant that leads to aberrant splicing and accounts for approximately 14% of disease-causing alleles in persons of northern European descent (Alasti et al. 2014). Across a selection of the available literature, the c.1001+1G>A has been identified in a total of 53 individuals with hearing loss or Pendred syndrome, including four homozygotes, 17 compound heterozygotes, and 32 heterozygotes where a second variant was not identified (Coyle et al. 1998; Bogazzi et al. 2000; Campbell et al. 2001; Fugazzola et al. 2002; Tsukamoto et al. 2003; Bogazzi et al. 2004; Pryor et al. 2005; Madden et al. 2007; Pera et al. 2008; Pourova et al. 2010). The c.1001+1G>A variant is absent from over 500 controls and is reported at a frequency of 0.00052 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the c.1001+1G>A variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000005088 SCV000485268 pathogenic Pendred syndrome 2016-02-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000239276 SCV000854902 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036418 SCV000893728 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000239276 SCV000935776 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 (rs80338849, ExAC 0.03%). This variant has been observed in combination with another SLC26A4 variant in individuals affected with Pendred syndrome (PMID: 9618167, 26744121, 24224479). ClinVar contains an entry for this variant (Variation ID: 4819). 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.
OMIM RCV000005088 SCV000025264 pathogenic Pendred syndrome 1998-07-01 no assertion criteria provided literature only
GeneReviews RCV000005088 SCV000040673 pathologic Pendred syndrome 2011-12-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477914 SCV000536905 pathogenic Enlarged vestibular aqueduct 2016-06-30 no assertion criteria provided research

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