Submissions for variant NM_000441.2(SLC26A4):c.919-2A>G

gnomAD frequency: 0.00018  dbSNP: rs111033313

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000169120	SCV000840527	pathogenic	Pendred syndrome	2018-09-20	reviewed by expert panel	curation	The filtering allele frequency of the c.919-2A>G variant in the SLC26A4 gene is 0.4% for East Asian chromosomes in the Genome Aggregation Database (91/18860 with 95% CI) , which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, the c.919-2A>G variant in SLC26A4 is predicted to cause the skipping of a biologically-relevant out-of-frame exon 8. This is then expected to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). Additionally, this variant has been detected in 16 patients with hearing loss in trans with more than 4 pathogenic variants (PM3_VeryStrong; PMID: 23151025). The c.919-2A>G variant in SLC26A4 has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; 10874637). Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PP1_Strong, PM3_VeryStrong, BS1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824767	SCV000060168	pathogenic	Rare genetic deafness	2011-02-01	criteria provided, single submitter	clinical testing	The 919-2A>G variant in SLC26A4 has been reported in over 400 individuals with n onsyndromic hearing loss or Pendred syndrome (Coucke 1999, Yong 2001, Park 2003, Tsukamoto 2003, Park 2005, Dai 2008). This variant was found to segregate with Pendred syndrome in two large families (Coucke 1999, Iwasaki 2006). In addition, is predicted to cause abnormal splicing because the nucleotide substitution occ urs in the invariant region of the splice consensus sequence. In summary, this v ariant meets our criteria to be classified as pathogenic.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000169120	SCV000267507	likely pathogenic	Pendred syndrome	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000414330	SCV000490809	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect; variant results in skipping of exon 8 and a new stop codon at position 348 (Lu et al., 2014); This variant is associated with the following publications: (PMID: 16711435, 20842945, 19786220, 23469187, 21811566, 25525159, 26100058, 20301640, 28505178, 28786104, 27308839, 28640090, 29106878, 28901477, 31442870, 30282152, 30589569, 30693673, 29234782, 31347505, 31035178, 30473558, 30036422, 31107121, 30268946, 29681450, 30554688, 31599023, 31980526, 32203226, 30896630, 32425884, 24338212, 15574297, 11502831, 21961810, 23151025, 27176802, 27498126, 24007330, 10874637, 28925492, 28981942, 28093008, 28964290, 30086623, 31415960, 30970410, 30898719, 30762457, 29921047, 29634755, 27729126, 27240500, 30733538, 30842343, 31692010, 31564438, 32574949, 29650690, 31914302, 31541171, 31827275, 30275481, 31656273, 15905611, 34426522, 32877901, 34170635, 33614372, 32447495, 33724713, 32645618, 33597575, 33638616, 25231367, 17718863, 30311386, 15679828, 14508505, 23958391)
Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	RCV000005112	SCV000611827	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2017-07-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000414330	SCV000700798	pathogenic	not provided	2016-11-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000036513	SCV000893726	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-12-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000414330	SCV000932353	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the SLC26A4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs111033313, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with Pendred syndrome or non-syndromic hearing loss (PMID: 10874637, 11502831). It is commonly reported in individuals of East Asian ancestry (PMID: 11502831, 16711435, 23958391, 24007330). This variant is also known as IVS8-2A>G and 1143-2A>G. ClinVar contains an entry for this variant (Variation ID: 4840). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 15574297). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169120	SCV001163092	pathogenic	Pendred syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000169120	SCV001194114	pathogenic	Pendred syndrome	2021-11-08	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.919-2A>G is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.919-2A>G has been observed in cases with relevant disease (PMID: 18641518). Functional assessments of this variant are not available in the literature. c.919-2A>G has been observed in population frequency databases (gnomAD: EAS 0.49%). In summary, NM_000441.1(SLC26A4):c.919-2A>G 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. ​
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000169120	SCV001244771	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) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA analysis using patient cells showed an out-of-frame skipping of exon 8 which resulted in a frameshift and a premature termination codon, and subsequent nonsense-mediated decay of the resulting protein (PMID: 15574297). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 103 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 very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with non-syndromic enlarged vestibular aqueduct and Pendred syndrome (ClinVar, PMID: 25372295). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169120	SCV001572510	pathogenic	Pendred syndrome	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.919-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 8 although low levels of normal transcript were also reported in tissues from patients homozygous for this variant (example Lee_2014). The variant allele was found at a frequency of 0.00036 in 251010 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00036 vs 0.0035), allowing no conclusion about variant significance. c.919-2A>G has been widely reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coucke_1999, Li_2012). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000414330	SCV002020689	pathogenic	not provided	2020-03-25	criteria provided, single submitter	clinical testing
3billion	RCV000005112	SCV002059131	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-01-03	criteria provided, single submitter	clinical testing	The variant was co-segregated with Deafness, autosomal recessive 4 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 10874637) (PP1_S). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000004840, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000365, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 23151025, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000169120	SCV003935266	pathogenic	Pendred syndrome	2020-05-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005112	SCV004201814	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-30	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000036513	SCV005417743	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome		criteria provided, single submitter	clinical testing	PVS1+PM3_VeryStrong+PP1_Strong+BS1
OMIM	RCV000005112	SCV000025288	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2009-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000169120	SCV000086787	not provided	Pendred syndrome		no assertion provided	literature only
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000005112	SCV000902365	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV000005112	SCV000994911	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment
The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	RCV000169120	SCV001438732	pathogenic	Pendred syndrome	2020-05-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169120	SCV001455804	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291247	SCV001479672	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414330	SCV001958199	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000414330	SCV001973484	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737136	SCV005361227	pathogenic	SLC26A4-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The SLC26A4 c.919-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported as causative for autosomal recessive Pendred syndrome and hearing loss with enlarged vestibular aqueducts (EVA) (described as c.1143-2A>G, Coucke et al. 1999. PubMed ID: 10874637; Yong et al. 2001. PubMed ID: 11502831; Li et al. 2012. PubMed ID: 23151025; described as IVS7A>G, Yang et al. 2005. PubMed ID: 15574297). This variant is reported in 0.51% of alleles in individuals of East Asian descent in gnomAD, and has been reported as the most common cause of deafness in East Asian populations (Li et al. 2012. PubMed ID: 23151025). RT-PCR experiments showed that this variant results in loss of exon 8 (Yang et al. 2005. PubMed ID: 15574297), and variants that disrupt the consensus splice acceptor site in SLC26A4 are expected to be pathogenic. This variant is interpreted as pathogenic.