Submissions for variant NM_000441.2(SLC26A4):c.916dup (p.Val306fs)

gnomAD frequency: 0.00001  dbSNP: rs768245266

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409855	SCV000485440	likely pathogenic	Pendred syndrome	2015-12-11	criteria provided, single submitter	clinical testing
Invitae	RCV000812506	SCV000952821	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val306Glyfs*24) 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 (rs768245266, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with non-syndromic hearing loss and Pendred syndrome (PMID: 14715652, 17718863, 21366435, 26252218). This variant is also known as 916_917insG and 916insG. ClinVar contains an entry for this variant (Variation ID: 370192). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000812506	SCV001167878	pathogenic	not provided	2020-06-22	criteria provided, single submitter	clinical testing	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; Published functional studies demonstrate a damaging effect on iodide transport (Gillam et al., 2004); This variant is associated with the following publications: (PMID: 30275481, 30896630, 31827275, 31581539, 30842343, 26252218, 14715652, 27240500, 20483489, 23302201, 17718863)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089561	SCV001244770	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-10-27	criteria provided, single submitter	clinical testing	A heterozygous duplication variant, NM_000441.1(SLC26A4):c.916dupG, has been identified in exon 7 of 21 of the SLC26A4 gene. This variant is predicted to cause a frameshift from amino acid position 306 and introduce a stop codon 24 residues downstream, NP_000432.1(SLC26A4):p.(Val306Glyfs*24), resulting in loss of protein function either through truncation (involving half of the protein including functional domains) or nonsense-mediated decay.This variant is present in the gnomAD database with a global frequency of 0.0014% (2 in 277028, 0 homozygotes) and in East Asian populations at a frequency of 0.02% (4 in 18862, 0 homozygotes). The variant has been previously described as pathogenic in multiple families withsevere to profoundhearing loss(ClinVar, Li, Q. et al. (2012), Lee, HJ. et al. (2014),Mori, K.et al. (2016), Wang, Q-J. et al. (2007),Jung, J. et al. (2017)). Based on current informationthis variant has been classified as PATHOGENIC.
Genome-Nilou Lab	RCV000409855	SCV002026721	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001089561	SCV004201806	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000409855	SCV002079981	pathogenic	Pendred syndrome	2020-12-02	no assertion criteria provided	clinical testing