ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.706C>G (p.Leu236Val) (rs111033242)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000411990 SCV000840500 likely pathogenic Pendred syndrome 2020-09-22 reviewed by expert panel curation The c.706C>G (p.Leu236Val) variant in SLC26A4 was identified in 0.026% (9/34592) of Latino chromosomes, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Pendred syndrome (PM2_Supporting; This variant has been detected in 1 proband with hearing loss in trans with a pathogenic variant, in 2 probands with hearing loss with a second pathogenic variant with phase unknown, and in the homozygous state in 1 proband with hearing loss (PM3_Strong; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5, ARUP internal data ClinVar SCV000605149.1, Chinese PLA General Hospital internal data, Molecular Otolaryngology and Renal Research Laboratories internal data). A different pathogenic missense variant (p.Leu236Pro) has been previously identified at this codon of SLC26A4, which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 4817). The variant has been reported to segregate with hearing loss in two affected family members (PP1; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5). At least one patient with a variant in this gene displayed features of hearing loss with temporal bone abnormality (PP4; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5). Of note, this variant has been suggested to constitute a haplotype with c.200C>G (p.Thr67Ser), which the Hearing Loss Expert Panel has classified as likely benign. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_Strong, PM5, PM2_Supporting, PP1, PP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824765 SCV000060159 likely pathogenic Rare genetic deafness 2018-08-02 criteria provided, single submitter clinical testing The p.Leu236Val variant in SLC26A4 has been identified 1 heterozygous individual with hearing loss (Chen 2011), 1 heterozygous individual with profound bilatera l hearing loss and multiple congenital anomalies (Tang 2015), in 1 presumed comp ound heterozygous individual with bilateral sensorineural hearing loss (phase no t confirmed; personal communication of ClinVar submitter, ClinVar ID 43565) and in 1 compound heterozygous Asian individual with hearing loss and bilateral temp oral bone abnormalities (LMM data). In the last case, it segregated with disease in the homozygous state in 2 distant relatives (5 meioses removed) with congeni tal hearing loss (LMM data). It has also been identified in 0.03% (9/33580) of L atino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa; dbSNP rs111033242). This variant also affects a residue that is the site of an established pathogenic variant (p.Leu236Pro; ClinVar ID 4817), su ggesting that changes at this position are not tolerated. Computational predicti on tools and conservation analysis suggest that the p.Leu236Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. It should be noted that this variant is often found in cis with the likely benign p.Thr67Ser variant. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Leu236Val variant is likely pathogenic. ACMG/AMP criteria applied: PM3, PM5, PP1_Moderate, PM2_Su pporting, BP4.
Counsyl RCV000411990 SCV000486635 likely pathogenic Pendred syndrome 2016-07-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508376 SCV000605149 uncertain significance not specified 2017-02-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036504 SCV000894404 likely pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV001561167 SCV001783711 likely pathogenic not provided 2021-05-20 criteria provided, single submitter clinical testing The L236V variant was classified as a likely pathogenic variant by ClinGen's Hearing Loss Expert Panel (ClinVar SCV000840500.1; Oza et al., 2018); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33885265, 31009165, 30113565, 21704276, 30268946, 25991456, 31581539, 33136026)

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