Submissions for variant NM_000441.2(SLC26A4):c.1905G>A (p.Glu635=)

gnomAD frequency: 0.00013  dbSNP: rs541538556

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666200	SCV000790453	uncertain significance	Pendred syndrome	2017-03-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000728322	SCV000855878	uncertain significance	not provided	2017-07-21	criteria provided, single submitter	clinical testing
Invitae	RCV000728322	SCV001091048	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779044	SCV002014807	likely benign	not specified	2021-10-08	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1905G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251196 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.1905G>A has been reported in the literature in individuals affected with enlarged vestibular aqueduct/hearing loss without strong evidence for causality (Dai_2008, Yuan_2009, Li_2014, Yuan_2012). These reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One lab classified the variant as likely benign while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV001785694	SCV002027351	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000666200	SCV002027362	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000728322	SCV002504031	likely benign	not provided	2021-05-11	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.