Submissions for variant NM_000441.2(SLC26A4):c.1614+1G>A

gnomAD frequency: 0.00001  dbSNP: rs111033312

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036451	SCV000060106	pathogenic	Rare genetic deafness	2015-07-09	criteria provided, single submitter	clinical testing	The c.1614+1G>A variant in SLC26A4 has been reported in 13 individuals with hear ing loss or Pendred syndrome, and 8 of them were compound heterozygous (Fugazzol a 2002, Blons 2004, Pera 2008, Pourova 2010, LMM unpublished data). This variant has also been identified in 3/66512 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033312). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic.
GeneDx	RCV000359760	SCV000329897	pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21704276, 30368370, 30651814, 30268946, 31589614, 18285825, 32645618, 15355436, 11919333, 31541171, 24105851, 33597575, 20128824, 20597900)
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	RCV000515698	SCV000611817	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000359760	SCV001230542	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs111033312, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with nonsyndromic enlarged vestibular aqueduct and hearing loss (PMID: 11919333, 15355436, 20128824, 20597900, 24105851). ClinVar contains an entry for this variant (Variation ID: 43516). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000515698	SCV002026950	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000984218	SCV002026952	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000984218	SCV002060395	pathogenic	Pendred syndrome	2021-11-03	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.1614+1G>A is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.1614+1G>A has been observed in cases with relevant disease (PMID: 15355436). Functional assessments of this variant are not available in the literature. c.1614+1G>A has been observed in population frequency databases (gnomAD: NFE 0.004%). In summary, NM_000441.1(SLC26A4):c.1614+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV002477084	SCV002789899	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2022-02-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000515698	SCV004201833	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-18	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000515698	SCV000902375	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000984218	SCV001459930	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing