Submissions for variant NM_000441.2(SLC26A4):c.415+4A>G

gnomAD frequency: 0.00010  dbSNP: rs368280107

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000608886	SCV000710862	uncertain significance	not specified	2016-12-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.415+4A>G variant in SLC26A4 has been reported in the compound heterozygous state with a s econd SLC26A4 variant in 1 Korean individual with hearing loss and enlarged vest ibular aqueducts (Park 2005). This variant has been identified in 2/10202 Afric an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs368280107); however, its frequency is not high enough to rule out a pathogenic role. This variant is located in the 5' splice region. Computat ional tools suggest an impact to splicing. However, this information is not pred ictive enough to determine pathogenicity. In summary, while the clinical signifi cance of this variant is uncertain, available data suggest that this variant is more likely to be pathogenic.
Counsyl	RCV000673210	SCV000798387	uncertain significance	Pendred syndrome	2018-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608886	SCV001983469	uncertain significance	not specified	2021-09-14	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.415+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; one predict the variant weakens a 5 prime donor site. However, one experimental study showed that this variant did not affect normal splicing (Lee_2019). The variant allele was found at a frequency of 8e-06 in 251052 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.415+4A>G has been reported in the literature in individuals affected with hearing loss (Park_2004). This report does not provide unequivocal conclusions about association of the variant with Pendred Syndrome. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001785679	SCV002026996	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000673210	SCV002026997	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV002298703	SCV002588058	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31033086, 15679828)