Submissions for variant NM_000441.2(SLC26A4):c.1924T>C (p.Ser642Pro) (rs397516423)

Total submissions: 6

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	2019-09-25	reviewed by expert panel	curation	The filtering allele frequency of the p.Ser642Pro variant in SLC26A4 is 0.467% (188/35420) for Latino chromosomes in gnomAD (BS1). The variant has been detected with another pathogenic SLC26A4 variant with unknown phase in 1 proband with sensorineural hearing loss and enlarged vestibular aqueducts (PM3_Supporting, PP4, SCV000060117.6, Laboratory for Molecular Medicine internal data). Additionally, computational prediction tools and conservation analysis suggest that the p.Ser642Pro variant may impact the protein (PP3). In summary, due to conflicting evidence, this variant has been classified as uncertain for autosomal recessive Pendred syndrome. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PM3_Supporting, PP4, PP3.
Laboratory for Molecular Medicine,Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000036462	SCV000345424	likely benign	not specified	2016-09-07	criteria provided, single submitter	clinical testing
Invitae	RCV000966198	SCV001113490	likely benign	not provided	2020-12-04	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina	RCV001159887	SCV001321634	uncertain significance	Deafness, autosomal recessive 4, with enlarged vestibular aqueduct	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.