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

Total submissions: 12

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