ClinVar Genomic variation as it relates to human health

Asn322Asp in Exon 08 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (18/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143002265).

This variant is associated with the following publications: (PMID: 30245029, 27771369, 21704276, 18368581, 25262649, 17309986, 23401162)

Variant summary: SLC26A4 c.964A>G (p.Asn322Asp) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 250902 control chromosomes, predominantly at a frequency of 0.0044 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.964A>G has been reported in the literature, primarily as an uninformative genotype (i.e. zygosity not specified), in individuals affected with hearing loss/enlarged vestibular aqueduct, without strong evidence for causality (e.g. Madden_2007, Chen_2011, Greinwald_2013). Therefore, 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. The following publications have been ascertained in the context of this evaluation (PMID: 21704276, 23401162, 17309986). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=3), or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely 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). 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.

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.

NM_000441.1(SLC26A4):c.964A>G(N322D) is a missense variant classified as a variant of uncertain significance in the context of Pendred syndrome. N322D has been observed in cases with relevant disease (PMID: 21704276, 23401162). Functional assessments of this variant are not available in the literature. N322D has been observed in population frequency databases (gnomAD: AFR 0.44%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.964A>G(N322D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).