Submissions for variant NM_000441.2(SLC26A4):c.1439T>A (p.Val480Asp)

dbSNP: rs1314376649

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NxGen MDx	RCV001374700	SCV001571612	uncertain significance	Pendred syndrome	2021-03-26	criteria provided, single submitter	clinical testing	This missense variant (c.1439T>A) in the first codon of exon 13 on SLC26A4 results in a similarly sized residue but changes from nonpolar to negatively charged (p.Val480Asp). This variant is not found in gnomAD exomes (PM2) and has been predicted to be pathogenic by numerous in silico models (PP3). This variant was first reported in Scott et al., PMID 10861298, in trans with L236P in a patient presenting non-syndromic hearing loss. Functional assessment of V480D in Xenopus laevis oocytes in the same report indicated significant residual activity that increased proportionally with V480D protein concentration.
Mendelics	RCV001374700	SCV002517414	likely pathogenic	Pendred syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307735	SCV002600574	uncertain significance	not specified	2022-10-19	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1439T>A (p.Val480Asp) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251364 control chromosomes. c.1439T>A has been reported in the literature as a biallelic compound heterozygous genotype in at-least one individual with features of Pendred syndrome with subsequent citations by others (example, Scott_2000, Campbell_2001, Gardner_2006, Gruber_2016, Dossena_2006, Pera_2008). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in Xenopus laevis oocytes (Scott_2000). The most pronounced variant effect results in a significantly lowered level of iodide and chloride transport as compared to wild-type (approximately 17-36%). However, this decrease in transport was restored/amplified with increased expression of the variant protein, indicating a retention of the ability to transport anions. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.