ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Benign. The Asp661Glu varia nt in SLC26A4 has been observed in one Asian individual with hearing loss and re tinal disease. This individual did not have a variant on the second copy of the SLC26A4 gene. Computational analyses (biochemical amino acid properties, homolog y, PolyPhen, SIFT, AlignGVGD) do not provide strong support for or against patho genicity. In summary, the clinical significance of this variant cannot be determ ined at this time; however, given the lack of association between SLC26A4 varian ts and retinal disease, the variant is more likley benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Observed heterozygous with no second SLC26A4 variant in multiple unrelated patients (Yuan et al., 2012; Huang et al., 2018; Fu et al., 2016; Yao et al., 2013); Observed in a patient with hearing loss in published literature who harbored a homozygous variant in the OTOA gene (Iwasa et al., 2019); Observed in trans with a pathogenic variant in the unaffected parent of a patient with hearing loss in published literature; the affected child harbored two SLC26A4 variants and did not inherit D661E (Yu et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29605365, 21704276, 31095577, 30086623, 23638949, 26886089, 18274916, 16952406, 25761933, 30245029, 23185506, 30762455)

Variant summary: SLC26A4 c.1983C>A (p.Asp661Glu) results in a conservative amino acid change located in the STAS (Sulphate Transporter and AntiSigma factor antagonist) domain (IPR002645) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0017 in the gnomAD database. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0035), allowing no conclusion about variant significance. The variant, c.1983C>A, has been reported in the literature in multiple heterozygous individuals who were affected with hearing loss (e.g. Schrijver_2006, Yuan_2012, Dahl_2013, Gu_2014, Iwasa_2019) or congenital hypothyroidism with normal hearing (e.g. Fu_2016, Zhang_2021), however, in some of these hearing loss cases co-occurrences with other (potentially) pathogenic biallelic variants in other genes have been reported, which could explain the phenotype (e.g. in the GJB2 gene, in Schrijver_2006 and Dahl_2013; and in the OTOF gene in Iwasa_2019), providing supporting evidence for a benign role. In addition, in a family, the proband who was affected with hearing loss, had two pathogenic SLC26A4 variants in compound heterozygous state, but didn't carry the variant, while the unaffected mother and unaffected sister both carried the c.1983C>A variant in trans with a pathogenic SLC26A4 variant (Yu_2019). On the other hand, a recent publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the p.Asp661Glu variant affected the ion transport function of the protein, but had no effect on the membrane location (Zhang_2021). Furthermore, the Deafness Variation Database (DVD), classified the variant as pathogenic, citing overlapping evidence utilized in the context of this evaluation (Azaiez_2018). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1) VUS (n=6), and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

NM_000441.1(SLC26A4):c.1983C>A(D661E) is a missense variant classified as a variant of uncertain significance in the context of Pendred syndrome. D661E has been observed in cases with relevant disease (PMID: 25761933, 23185506, 23638949). Functional assessments of this variant are not available in the literature. D661E has been observed in population frequency databases (gnomAD: EAS 0.16%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.1983C>A(D661E) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.