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

gnomAD frequency: 0.00005  dbSNP: rs111033242

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000411990	SCV000840500	pathogenic	Pendred syndrome	2024-10-16	reviewed by expert panel	curation	The c.706C>G variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by valine at amino acid 236 (p.Leu236Val). The variant was identified in 0.01833% (11/59998) of admixed American alleles, which is the highest population minor allele frequency in gnomAD v4.1.0 (PM2_Supporting and BS1 are not met). This variant has been detected in 3 probands in trans with a pathogenic variant, in 5 probands in phase unknown with a pathogenic variant, and in the homozygous state in 3 probands, all of whom had hearing loss and/or inner ear malformations consistent with Pendred syndrome. The variant was also identified with a pathogenic splice site variant in 2 probands (PM3_VeryStrong; 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, Revvity ClinVar SCV002023538.3GeneDx internal data ClinVar SCV001783711.3, Invitae internal data ClinVar SCV002234501.3). This variant was seen in two probands with no second variant identified whose phenotypes were consistent with Pendred syndrome (PMID: 34410491, 34515852), as well as in one proband with enlarged vestibular aqueduct who was compound heterozygous with a likely pathogenic variant in phase unknown (PP4; PMID: 36703223). 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). Additionally, the variant was seen in an adult with deafness who had two pathogenic GJB2 variants in trans (Revvity internal data ClinVar SCV002023538.3). The variant has been reported to segregate with hearing loss in two affected family members (PP1_Moderate; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PM5, PP1_Moderate, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024)
Laboratory for Molecular Medicine, Mass General Brigham 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 dinstitute.org; 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	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-05-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001561167	SCV001783711	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25991456, 21704276, 31009165, 33885265, 34410491, 31581539, 33924653, 33136026, 30113565, 30268946, 9618166, 9618167, 25999548)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798756	SCV001984740	likely pathogenic	Deafness	2024-10-04	criteria provided, single submitter	research	PM2_Supporting, PM3_Strong, PM5, PP1, PP4
Revvity Omics, Revvity	RCV001561167	SCV002023538	likely pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001561167	SCV002234501	pathogenic	not provided	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 236 of the SLC26A4 protein (p.Leu236Val). This variant is present in population databases (rs111033242, gnomAD 0.03%). This missense change has been observed in individual(s) with deafness, often in combination with p.Thr67Ser. However, this variant has also been observed without Thr67Ser in affected individual(s) (PMID: 21704276, 25991456; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43565). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Leu236 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618166, 10861298, 12354788, 15689455, 18310264). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473271	SCV004201825	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724763	SCV005337480	likely pathogenic	SLC26A4-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The SLC26A4 c.706C>G variant is predicted to result in the amino acid substitution p.Leu236Val. This variant has been reported in the homozygous state in four unrelated patients with hearing loss and enlarged vestibular aqueduct (EVA) (Chiong et al. 2018. PubMed ID: 30113565). Additionally, a different substitution at this amino acid position is well documented to be pathogenic (p.Leu236Pro; https://www.ncbi.nlm.nih.gov/clinvar/variation/4817/). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/43565/). This variant is interpreted as likely pathogenic.