Submissions for variant NM_000441.2(SLC26A4):c.1924T>C (p.Ser642Pro)

gnomAD frequency: 0.00029  dbSNP: rs397516423

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001004781	SCV001164265	uncertain significance	Pendred syndrome	2022-10-31	reviewed by expert panel	curation	The c.1924T>C variant in SLC26A4 is a missense variant predicted to cause the substitution of serine by proline at amino acid 642 (p.Ser642Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005308 (188/35420 alleles) in Latio/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.724, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in at least one individual with Pendred syndrome who was reported to have a second pathogenic SLC26A4 variant with an unknown phase (0.5 PM3 points, SCV000060117.6.6) (PM3_Supporting). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, SCV000060117.6.6). In summary, due to conflicting evidence, this variant has been classified as uncertain for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: BS1, PP3, PM3_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036462	SCV000060117	uncertain significance	not specified	2018-06-08	criteria provided, single submitter	clinical testing	The p.Ser642Pro variant in SLC26A4 has been previously identified by our laborat ory in three Hispanic individuals with hearing loss, one of whom had a second pa thogenic SLC26A4 variant and was reported to have EVA. This variant has been ide ntified in 0.5% (175/34396) of Latino chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516423), which is a f requency high enough to suggest that it may be benign. Computational prediction tools and conservation analyses suggest that this variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of this variant is uncertain. ACMG/AMP crit eria applied: PM3, PP3, PP4, BS1.
Eurofins Ntd Llc (ga)	RCV000036462	SCV000345424	likely benign	not specified	2016-09-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000966198	SCV001113490	likely benign	not provided	2024-12-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001004781	SCV001321633	uncertain significance	Pendred syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001159887	SCV001321634	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000966198	SCV001816539	likely benign	not provided	2021-01-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21704276)
PreventionGenetics, part of Exact Sciences	RCV004534764	SCV004728539	likely benign	SLC26A4-related disorder	2020-01-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).