ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1003T>C (p.Phe335Leu) (rs111033212)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824769 SCV000060075 pathogenic Rare genetic deafness 2018-09-06 criteria provided, single submitter clinical testing The p.Phe335Leu variant in SLC26A4 has been reported in more than 25 probands wi th hearing loss, at least 19 of whom had temporal bone abnormalities, and at lea st 6 of whom had a second pathogenic variant in SLC26A4 (Campbell 2001, Prasad 2 004, Pryor 2005, Madden 2007, Samanich 2007, Yang 2007, Pera 2008, Choi 2009, Da i 2009, Yang 2009, Pourova 2010, Rodriguez 2010, Chattaraj 2013, Landa 2013, Soh 2015, Likar 2018, LMM data). The variant also segregated with hearing loss and EVA in at least 1 affected family member (Pera 2008). Other variants at this pos ition, p.Phe335Ser and p.Phe335Val, have been detected in individuals with heari ng loss (Madden 2007, Nanose 2018), suggesting that changes to this position may not be tolerated. Furthermore, in vitro functional studies provide some evidenc e that the p.Phe335Leu variant may impact protein function (Choi 2009). This var iant has also been identified in 0.25% (77/30778) of South Asian chromosomes, in cluding 1 homozygote, by the Genome Aggregation Database (http://gnomAD.broadins Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and it is not known if individuals with hearing loss were excluded from the populati on studies included in gnomAD. In addition, a case-control comparison using Chi- squared analysis revealed a statistically significantly difference between the n umber of cases with the variant versus controls (p-value of <0.0001). In summary , despite its high frequency in the general population, this variant meets crite ria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AM P criteria applied: PM3_Very Strong, PP1, PS3_P, PP3, BS1_Supporting.
GeneDx RCV000656976 SCV000565574 likely pathogenic not provided 2017-11-21 criteria provided, single submitter clinical testing The F335L variant has been reported in the heterozygous state in individuals with dilated vestibular aqueduct (Campbell et al., 2001; Pryor et al., 2005; Muskett et al., 2015). Functional studies show F335L led to reduced protein activity compared to wild type, but this activity was substantially greater than null controls (Choi et al., 2009). The F335L variant is observed in 77/30778 (0.25%) alleles, from individuals of South Asian background, including one homozygous individual, in the ExAC dataset (Lek et al., 2016). The F335L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (F335S), as well as in nearby residues (G334W, G334V, G334A) 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. Therefore, based on the currently available information, we consider F335L to be a likely pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000483689 SCV000605152 likely pathogenic not specified 2017-04-10 criteria provided, single submitter clinical testing
Counsyl RCV000576732 SCV000678181 likely pathogenic Pendred syndrome 2017-06-14 criteria provided, single submitter clinical testing F335L is primarily associated with hearing loss and temporal bone abnormalities without thyroid-associated symptoms.
Fulgent Genetics,Fulgent Genetics RCV000036420 SCV000893729 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779523 SCV000916170 likely pathogenic SLC26A4-Related Disorders 2018-12-13 criteria provided, single submitter clinical testing The SLC26A4 c.1003T>C (p.Phe335Leu) missense variant has been identified in a compound heterozygous state in two siblings with SLC26A4-related disorders, and in a heterozygous state in at least 17 individuals in whom a second variant was not identified (Campbell et al. 2001; Albert et al. 2006; Madden et al. 2007; Yang et al. 2007; Pera et al. 2008; Choi et al. 2009; Pourová et al. 2010; Landa et al. 2013; Rendtorff et al. 2013). The compound heterozygous siblings were described with clinical features of hearing loss and enlarged vestibular aqueduct (EVA), where one of the siblings had bilateral EVAs and the other sibling had unilateral EVA. Most of the heterozygous probands presented with hearing loss with EVA, and the p.Phe335Leu variant was first identified in these probands through single-gene analyses of SLC26A4. In many probands with SLC26A4-related disorders, a second disease-causing variant is not identified (Yang et al. 2009). Digenic inheritance of heterozygous variants in SLC26A4 and KCNJ10 in association with hearing loss has been reported, and the p.Phe335Leu variant has been reported in a heterozygous state in two probands who also carried a KCNJ10 variant in a heterozygous state (Yang et al. 2009; Landa et al. 2013). The p.Phe335Leu variant is reported at a frequency of 0.00307 in the South Asian population of 1000 Genomes. Functional studies showed that the SLC26A4 protein carrying the p.Phe335Leu variant traffics to the plasma membrane in a manner indistinguishable from wild type protein and has substantial residual activity, but has a reduced Cl−/I− exchange rate constant (Choi et al. 2009). Based on the collective evidence, the p.Phe335Leu variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000576732 SCV000993594 likely pathogenic Pendred syndrome 2018-10-22 criteria provided, single submitter research
OMIM RCV000005114 SCV000025291 pathogenic Enlarged vestibular aqueduct 2009-05-01 no assertion criteria provided literature only

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