Submissions for variant NM_000441.2(SLC26A4):c.2089+1G>A

gnomAD frequency: 0.00003  dbSNP: rs727503430

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151908	SCV000200416	pathogenic	Rare genetic deafness	2014-04-11	criteria provided, single submitter	clinical testing	The 2089+1G>A variant in SLC26A4 has been previously identified in two individua ls with Pendred syndrome and segregated with disease in an affected sibling of one of these individuals (Blons 2004, Banghova 2008). This variant was absent fr om large population studies. The variant occurs in the invariant region (+1/2) o f the 5? splice consensus sequence and is predicted to cause altered splicing le ading to an abnormal or absent protein. In summary, this variant meets our crite ria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
GeneDx	RCV000492847	SCV000582142	pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing	The c.2089+1G>A variant in the SLC26A4 gene has been reported previously in the presence of another SLC26A4 variant, in individuals with Pendred syndrome, exhibiting sensorineural hearing loss, vestibular aqueductal enlargement and both with and without thyroid involvement (Blons et al., 2004; Banghova et al., 2008; Ladsous et al., 2014). This splice site variant destroys the canonical splice donor site in intron 18. 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.2089+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2089+1G>A as a pathogenic variant.
Invitae	RCV000492847	SCV000944137	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 18 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs727503430, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 2422447, 15355436). ClinVar contains an entry for this variant (Variation ID: 165263). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000477837	SCV002026966	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000411928	SCV002026967	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411928	SCV002570601	pathogenic	Pendred syndrome	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.2089+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 222764 control chromosomes (gnomAD). The variant, c.2089+1G>A, has been reported in the literature in homozygous and compound heterozygous state in individuals affected with hearing loss, with- or without the thyroid signs that are characteristic for Pendred Syndrome (e.g. Albert_2006, Ladsous_2014, Sheppard_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000477837	SCV004201917	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-06-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000411928	SCV000485725	likely pathogenic	Pendred syndrome	2016-02-02	no assertion criteria provided	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477837	SCV000536772	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2015-09-25	no assertion criteria provided	research
Natera, Inc.	RCV000411928	SCV002080020	pathogenic	Pendred syndrome	2020-10-16	no assertion criteria provided	clinical testing