Submissions for variant NM_000441.2(SLC26A4):c.964A>G (p.Asn322Asp)

gnomAD frequency: 0.00133  dbSNP: rs143002265

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036514	SCV000060169	likely benign	not specified	2012-05-07	criteria provided, single submitter	clinical testing	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000956518	SCV001103284	likely benign	not provided	2024-12-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164699	SCV001326840	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000674464	SCV001326841	uncertain significance	Pendred syndrome	2017-04-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000956518	SCV001768093	likely benign	not provided	2020-10-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30245029, 27771369, 21704276, 18368581, 25262649, 17309986, 23401162)
Genome-Nilou Lab	RCV001164699	SCV002027051	likely benign	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000674464	SCV002027062	likely benign	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000674464	SCV002060374	uncertain significance	Pendred syndrome	2021-10-20	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036514	SCV003928979	likely benign	not specified	2023-04-27	criteria provided, single submitter	clinical testing	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.
Natera, Inc.	RCV000674464	SCV001459863	uncertain significance	Pendred syndrome	2020-01-07	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000956518	SCV001979291	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000956518	SCV001980216	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534768	SCV004726956	likely benign	SLC26A4-related disorder	2023-05-10	no assertion criteria provided	clinical testing	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).