ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.707T>C (p.Leu236Pro) (rs80338848)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824766 SCV000060160 pathogenic Rare genetic deafness 2017-05-04 criteria provided, single submitter clinical testing The p.Leu236Pro variant in SLC26A4 has been reported in at least 15 individuals with either nonsyndromic hearing loss or Pendred syndrome who were homozygous or compound heterozygous, and it segregated in 4 affected family members from 2 fa milies (Busi 2012, Pryor 2005, Pourova 2010, Siem 2010, Van Hauwe 1998, LMM data ). One in vitro functional analysis study suggests the variant may impact normal intracellular trafficking of the protein (Rotman-Pikielny 2002). The p.Leu236Pr o variant has been identified in 0.1% (78/126638) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 80338848). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on bi-allelic occurrences in multiple affected indi viduals, segregation studies, functional evidence, and low frequency in the gene ral population. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Sup porting.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000524013 SCV000331545 pathogenic not provided 2017-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000524013 SCV000616878 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The L236P variant has been published previously in association with SLC26A4-related disorders (Van Hauwe et al., 1998; Sloan-Heggen et al., 2016). The variant is observed in 78/126638 (0.062%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). L236P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown L236P impairs proper localization of the SLC26A4 protein as well as iodide and chloride transport (Scott et al., 2000; Yoon et al., 2008). In summary, we consider this variant to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000036505 SCV000893725 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779522 SCV000916169 pathogenic SLC26A4-Related Disorders 2018-09-21 criteria provided, single submitter clinical testing The SLC26A4 c.707T>C (p.Leu236Pro) missense variant is well described in the literature and is one of the three most common pathogenic variants in SLC26A4, which together account for 50% of the disease-causing alleles in probands with Pendred syndrome of northern European descent (Alasti et al. 2014; Tsukada et al. 2015). Across a selection of available literature, the p.Leu236Pro variant has been reported in at least four individuals in a homozygous state, 13 individuals in a compound heterozygous state, and one individual in a heterozygous state, all affected with Pendred syndrome (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001). The variant has also been reported in individuals affected with hearing loss, including two in a compound heterozygous state and five in a heterozygous state (Yan et al. 2017). Campbell et al. (2001) demonstrated segregation with disease in at least one multiplex family with temporal bone abnormalities. Haplotype analysis suggests a common founder effect for this variant (van Hauwe et al. 2008; Coyle et al. 1998). The p.Leu236Pro variant was absent from 257 control individuals (van Hauwe et al. 1998; Coyle et al. 1998; Campbell et al. 2001; Yan et al. 2017) and is reported at a frequency of 0.00105 in the European American population of the Exome Sequencing Project. Functional studies by Rotman-Pikielny et al. (2002) demonstrated that the variant protein is retained in the endoplasmic reticulum (ER) whereas the wild type protein targets to the plasma membrane. Yoon et al. (2008) confirmed the initial localization of the p.Leu236Pro variant protein in the ER and showed that after time, the protein was concentrated at the centrosome. They further determined that Cl-/HCO3- ion exchange activity of the variant protein was notably decreased, and that the variant was not temperature sensitive. Based on collective evidence, the p.Leu236Pro 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 RCV000524013 SCV000958105 pathogenic not provided 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 236 of the SLC26A4 protein (p.Leu236Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs80338848, ExAC 0.06%). This variant has been observed as homozygous or in combination a pathogenic in several individuals affected with Pendred syndrome and hearing loss (PMID: 9618166, 15689455, 20553101, 20597900, 26969326). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 4817). Experimental studies have shown that this missense leads to subcellular protein mislocalization and loss of funtion (PMID: 18310264, 12354788, 10861298). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005086 SCV000993593 pathogenic Pendred syndrome 2018-10-22 criteria provided, single submitter research
Myriad Women's Health, Inc. RCV000005086 SCV001193872 pathogenic Pendred syndrome 2019-11-12 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.707T>C(L236P) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 9618167, 9618166, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.707T>C(L236P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001089560 SCV001244769 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-07-12 criteria provided, single submitter clinical testing The NM_000441.1(SLC26A4):c.707T>C missense variant was identified in exon 6 of SLC26A4. This substitution creates a moderate amino acid change from a leucine to a proline at position 236, NP_000432.1(SLC26A4):p.(Leu236Pro). The leucine at this position has high conservation (100 vertebrates, UCSC). In silico tools predict this variant to be deleterious (Polyphen, SIFT, CADD, Mutation Taster). This variant is present in the gnomAD population database at a frequency of 0.03% and it has been previously reported in patients with autosomal recessive Pendred syndrome (ClinVar/Deafness Variation Database). It is situated in a sulfate transporter domain. Additionally, functional studies show that this variant causes the protein to be retained intracellularly and is rapidly transported for endoplasmic reticulum associated degradation (Yoon JS. et al., (2008) J Med Genet). Based on current information and in association with the NM_000441.1(SLC26A4):c.1001+1G>A slice variant, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000524013 SCV001250491 pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375179 SCV001571785 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Supporting, BP4_Supporting
OMIM RCV000005086 SCV000025262 pathogenic Pendred syndrome 2008-07-01 no assertion criteria provided literature only
GeneReviews RCV000005086 SCV000040675 pathologic Pendred syndrome 2011-12-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000005086 SCV001455801 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000524013 SCV001551437 pathogenic not provided no assertion criteria provided clinical testing The SLC26A4 p.L236P variant has been reported in multiple homozygous or compound heterozygous individuals with hearing loss or hearing impairment (Yan_2017_PMID:28273078; Tang_2015_PMID:25991456; Pryor_2005_PMID:15689455; Pourova_2010_PMID:20597900; Busi_2012_PMID:22717225; Campbell_2001_PMID:11317356; Siem_2010_PMID:20553101; Van Hauwe_1998_PMID:9618166). The variant was identified in dbSNP (ID: rs80338848) and ClinVar (classified as pathogenic by Invitae, GeneDx, EGL Genetic Diagnostics and nine other submitters). The variant was identified in control databases in 83 of 282766 chromosomes (0 homozygous) at a frequency of 0.0002935, and was observed at the highest frequency in the European (non-Finnish) population in 77 of 129104 chromosomes (freq: 0.0005964) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.L236 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies have shown that this variant causes protein mislocalization and impaired iodide/chloride transport activity compared to wild type (Scott_2000_PMID:10861298, Rotman-Pikielny_2002_PMID:12354788, Yoon_2008_PMID:18310264). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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