ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2168A>G (p.His723Arg) (rs121908362)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036477 SCV000060132 pathogenic Rare genetic deafness 2011-07-28 criteria provided, single submitter clinical testing The His723Arg variant in SLC26A4 has been reported in 37 probands with hearing l oss and enlarged vestibular aqueducts (EVA) or Pendred syndrome (Wu 2005, Van Ha uwe 1998, Lee 2008, Asakura 2010, Cho 2006, Dai 2008, Hu 2007, Ishihara 2010, Ki m 2009, Park 2003, Reyes 2009, Tsukamoto 2003, Usami 1999, Yoon 2008). Many of t hese probands were homozygous or compound heterozygous and the variant has segre gated with disease in several families. Furthermore, functional studies revealed that the His723Arg variant disrupts the normal cellular localization and ion tr ansport activity of the protein (Yoon 2008, Ishihara 2010). In summary, this var iant meets our criteria to be classified as pathogenic.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000005095 SCV000267506 likely pathogenic Pendred syndrome 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000480319 SCV000568753 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing The H723R variant in the SLC26A4 gene has been published previously in association with Pendred syndrome and hearing loss, including multiple affected homozygotes (Van Hauwe et al., 1998; Yong et al., 2001; Lee et al., 2014; Sagong et al., 2017). The variant is observed in 31/18868 (0.16%) alleles from individuals of East Asian background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). This substitution occurs at a position within the STAS domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that H723R prevents proper localization of the SLC26A4 protein to the cell membrane, and decreases protein activity in comparison to wild type (Yoon et al., 2008). Missense variants in the same residue (H723Y/D) and in nearby residues (F718S, T721M, D724N/G, A725P, L727F, Y728H) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret H723R as a pathogenic variant.
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000005094 SCV000611824 pathogenic Enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000480319 SCV000886131 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing The c.2168A>G; p.His723Arg (rs121908362) is one of commonly observed variants reported in patients with Pendred Syndrome and hearing loss across the Asian population (Van Hauwe, 1998; Ishihara, 2010; Sagong, 2013; Asakura, 2010; Li, 2016). Lee (2014) noted that patients with two copies of the p.His723Arg variant had poorer hearing and higher proportion of incomplete cochlear turns (Mondini structures) compared to compound heterozygotes with a single copy and a different SLC26A4 variant. Cell-based and biochemical experiments further demonstrated that p.His723Arg polypeptides are impaired at reaching the plasma membrane and exhibit abnormal ion exchange activity that can be rescued at low temperature (Yoon, 2008). This variant is listed in the Genome Aggregation Database (gnomAD) in the East Asian population at a frequency of 0.16 percent (identified on 31 out of 18,868 chromosomes with 0 homozygotes) and is reported to the ClinVar database as a pathogenic/likely pathogenic variant (Variation ID: 4825). The histidine at position 723 is highly conserved across 12 species (Alamut v2.9.0), and computational analyses of the effects of the p.His723Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether the p.His723Arg variant is pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778813 SCV000915193 pathogenic SLC26A4-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection of the available literature, it has been identified in a homozygous state in 26 patients, in a compound heterozygous state in 67 patients, and in a heterozygous state in 19 patients, including those with Pendred syndrome and autosomal recessive nonsyndromic hearing loss with enlarged vestibular aqueduct (Tsukamoto et al. 2003; Park et al. 2005; Cho et al. 2006; Kim et al. 2009; Reyes et al. 2009; Miyagawa et al. 2014; Lu et al. 2015; Tsukada et al. 2015). Family studies have demonstrated inheritance of the variant from unaffected heterozygous parents. The p.His723Arg variant was identified in a heterozygous state in three of 1024 Asian control alleles (Park et al. 2003; Yuan et al. 2012; Miyagawa et al. 2014) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. Functional studies in HEK 293 and HeLa cells showed the variant causes the protein to be retained in the endoplasmic reticulum rather than localized to the cell membrane and significantly reduces chloride bicarbonate ion exchange function, consistent with the proposed disease mechanism. The defects were rescued by incubation at low temperature, suggesting they may be due to protein misfolding (Yoon et al. 2008). Based on the collective evidence, the p.His723Arg variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000480319 SCV000939369 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 723 of the SLC26A4 protein (p.His723Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs121908362, ExAC 0.2%). This variant has been observed to segregate with Pendred syndrome in several families and has been observed with another SLC26A4 variant in unrelated individuals affected with Pendred syndrome or clinical features of this condition (PMID: 24338212, 22884721, 17322586, 11405873, 23705809, 20583162). ClinVar contains an entry for this variant (Variation ID: 4825). This variant has been reported to affect SLC26A4 protein trafficking in vitro (PMID: 20583162). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005094 SCV000025270 pathogenic Enlarged vestibular aqueduct 2008-07-01 no assertion criteria provided literature only
OMIM RCV000005095 SCV000025271 pathogenic Pendred syndrome 2008-07-01 no assertion criteria provided literature only
GeneReviews RCV000005094 SCV000086786 pathologic Enlarged vestibular aqueduct 2011-12-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000005095 SCV000678160 pathogenic Pendred syndrome 2017-06-15 no assertion criteria provided clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000005094 SCV000902362 likely pathogenic Enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control

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