Submissions for variant NM_000441.2(SLC26A4):c.697G>C (p.Val233Leu)

gnomAD frequency: 0.00004  dbSNP: rs397516431

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036503	SCV000060158	uncertain significance	not specified	2011-03-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Val233Leu v ariant in SLC26A4 has been reported as a compound heterozygous variant with anot her pathogenic variant in a Chinese proband with hearing loss and enlarged vesti bular aqueduct (EVA) and was absent in 200 race matched control chromosomes (Hu, 2007). However, it was not reported whether this variant was in trans with the second SLC26A4 variant. Furthermore, computational analyses (biochemical amino a cid properties, homology, PolyPhen, SIFT, AlignGVGD) do not provide strong suppo rt for or against pathogenicity. In summary, the clinical significance of this v ariant cannot be determined with certainty at this time.
Counsyl	RCV000670566	SCV000795433	uncertain significance	Pendred syndrome	2017-11-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001375688	SCV002027002	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000670566	SCV002027003	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV002513385	SCV003263323	likely pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 233 of the SLC26A4 protein (p.Val233Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital hypothyroidism and/or deafness (PMID: 17443271, 25788563, 26886089, 28215547, 32459320, 34170635). 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: 43564). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV002513385	SCV003825640	uncertain significance	not provided	2020-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036503	SCV003928977	uncertain significance	not specified	2023-04-03	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.697G>C (p.Val233Leu) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251476 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0001 vs 0.0035), allowing no conclusion about variant significance. c.697G>C has been reported in the literature as a compound heterozygous genotype in individuals affected with enlarged vestibular aqueduct (EVA) (example, Hu_2007, Tian_2021) as well as a non-informative genotype in settings of multigene panel testing for hearing loss, congenital hypothyroidism (CH) (example, Nishio_2015, Fan_2017, Chen_2022, Yamaguchi_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV000670566	SCV001455800	uncertain significance	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
Precision Medicine Center, Zhengzhou University	RCV001375688	SCV001572609	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4		no assertion criteria provided	research	GnomAD genomes East Asian allele frequency =0.001353>0.0007, not apply to PM2 PM3_Strong: Pathogenic mutation confirmed in trans in one patient and phase unknown in 4 patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene