Submissions for variant NM_000441.2(SLC26A4):c.1547dup (p.Ser517fs)

dbSNP: rs786204450

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169076	SCV000220245	likely pathogenic	Pendred syndrome	2014-04-15	criteria provided, single submitter	literature only
Invitae	RCV001214282	SCV001385957	pathogenic	not provided	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser517Phefs*10) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs776972633, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with non-syndromic hearing loss (PMID: 19786220, 20842945, 21704276). ClinVar contains an entry for this variant (Variation ID: 188759). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169076	SCV002026941	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000169076	SCV002768258	pathogenic	Pendred syndrome	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with enlarged vestibular aqueduct (PMID: 27997596, PMID: 24612839, ClinVar). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV001822853	SCV004201824	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001214282	SCV005081350	pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	Identified in additional patients with sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 27247933, 30733538, 35939872, 36597107); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34416374, 21961810, 20842945, 19786220, 12676893, 24341454, 23918157, 23151031, 23151025, 21704276, 30733538, 30275481, 34170635, 32447495, 35314707, 36126472, 36597107, 27247933, 33199029, 35982127, 27997596, 35939872)
WangQJ Lab, Chinese People's Liberation Army General Hospital	RCV001822853	SCV001762423	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-07-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169076	SCV002080000	pathogenic	Pendred syndrome	2020-02-11	no assertion criteria provided	clinical testing