Submissions for variant NM_000441.2(SLC26A4):c.412G>T (p.Val138Phe) (rs111033199)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel,	RCV000005106	SCV000840515	pathogenic	Pendred syndrome	2018-09-19	reviewed by expert panel	curation	The p.Val138Phe variant in SLC26A4 has been detected in over 4 patients with Pendred syndrome or hearing loss with enlarged vestibular aqueducts who harbored a pathogenic or suspected pathogenic variant in trans with p.Val138Phe (PM3_VS; PMID: 17503324, 15689455, 20597900, 18285825, 23965030, 24224479, 21551164, 23273637, 12788906, 16570074). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 25999548, 23336812, 26683941). The p.Val138Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID: 12788906). The allele frequency of the p.Val138Phe variant in the SLC26A4 gene is 0.03% (38/126540) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). Computational prediction tools and conservation analysis suggest that the p.Val138Phe variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA and/or Mondini malformation which are consistent with Pendred syndrome (PP4; PMID: 12788906, 23273637). A functional study performed in HeLa and human embryonic kidney cell lines demonstrated that pendrin harboring the p.Val138Phe variant did not localize to the cell membrane. However, there was no effect on iodide efflux (PS3_P; PMID: 11932316). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome/EVA based on the ACMG/AMP criteria applied: PM3_VS, PS4, PP1_M, PM2_Supporting, PP3, PP4, PS3_P.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000824762	SCV000060148	pathogenic	Rare genetic deafness	2017-10-24	criteria provided, single submitter	clinical testing	The p.Val138Phe variant in SLC26A4 has been reported in more than 20 individuals with clinical features of Pendred syndrome or DFNB4 hearing loss, at least 10 o f whom were homozygous or compound heterozygous (Borck 2003, Campbell 2001, Coyl e 1998, de Moraes 2013, Gonzalez Trevino 2001, Kandasamy 2011, Pourova 2010, Pry or 2005, Taylor 2002, Van Hauwe 1998, LMM data). It has been identified in 38/12 6540 European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; rs111033199); however, this low frequency is consistent with the carrier frequency in the general population. In vitro functional studi es provide some evidence that the p.Val138Phe variant may impact protein functio n (Taylor 2002). In summary, this variant meets criteria to be classified as pat hogenic for Pendred syndrome or nonsyndromic hearing loss in an autosomal recess ive manner. ACMG/AMP Criteria applied: PM3_Strong, PS4, PS1_Support (Richards 20 15).
Counsyl	RCV000005106	SCV000220136	pathogenic	Pendred syndrome	2014-03-02	criteria provided, single submitter	literature only
Illumina Clinical Services Laboratory,Illumina	RCV000272658	SCV000466080	pathogenic	SLC26A4-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the SLC26A4 c.412G>T (p.Val138Phe) missense variant has been identified in a total of 23 patients with hearing loss or Pendred syndrome, including in four in a homozygous state, 14 in a compound heterozygous state and five in a heterozygous state in whom a second variant was not identified. The variant was also found in a heterozygous state in at least two unaffected family members (Van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Gonzales-Trevino et al. 2001; Taylor et al. 2002; Borck et al. 2003; Pryor et al. 2005; Pera et al. 2008; Kandasamy et al. 2011; Landa et al. 2013). Segregation with disease is reported to have been shown in several families (Van Hauwe et al. 1998; Gonzales-Trevino et al. 2001). The variant was absent from 214 controls and is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Val138 residue is conserved among several other related sulfate transporter genes from different species. Functional studies have shown that the p.Val138Phe variant protein is retained in the endoplasmic reticulum and fails to reach the cell membrane leading to loss of protein activity (Taylor et al. 2002). Based on the collective evidence, the p.Val138Phe 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.
GeneDx	RCV000413949	SCV000490808	pathogenic	not provided	2018-09-27	criteria provided, single submitter	clinical testing	The V138F missense variant in the SLC26A4 gene has been reported in the homozygous and compound heterozygous state in numerous individuals with Pendred syndrome or non-syndromic hearing loss with or without enlarged vestibular aqueducts (Van Hauwe et al., 1998; Borck et al., 2003; Kandasamy et al., 2011; de Moraes et al., 2013; Sloan-Heggen et al., 2016). Although the V138F variant is observed in 22/66,056 alleles (0.033%) from individuals of non-Finnish European background in the ExAC dataset, no homozygous control individuals were reported (Lek et al., 2016). The V138F variant is a semi-conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Valine are tolerated across species. In vitro studies of the V138F variant indicated that this variant form of pendrin is retained in the endoplasmic reticulum and fails to properly assemble at the cell membrane, suggestive of aberrant protein processing (Taylor et al., 2002). We therefore interpret V138F as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics	RCV000036493	SCV000611320	pathogenic	Enlarged vestibular aqueduct; Pendred syndrome	2017-05-18	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000413949	SCV000862124	pathogenic	not provided	2018-07-11	criteria provided, single submitter	clinical testing
Invitae	RCV000413949	SCV000937942	pathogenic	not provided	2018-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine with phenylalanine at codon 138 of the SLC26A4 protein (p.Val138Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs111033199, ExAC 0.03%). This variant has been reported in the homozygous or compound heterozygous state in many individuals and families affected with Pendred syndrome (PMID: 12788906, 24224479, 21551164, 9618166, 11932316, 26969326) or non-syndromic hearing loss with an enlarged vestibular aqueduct (PMID: 23273637).  ClinVar contains an entry for this variant (Variation ID: 4835). Experimental studies have shown that SLC26A4 protein harboring this missense change is retained in the endoplasmic reticulum and fails to localize to the cell membrane in vitro (PMID: 11932316). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000005106	SCV000025282	pathogenic	Pendred syndrome	2003-06-01	no assertion criteria provided	literature only