rs111033313

Positions:

• chr7-107683453-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PP1_Strong BS1 PVS1 PM3

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261445/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:25 O:2
• Conservation: PhyloP100: 8.43

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.919-2A>G		splice_acceptor_variant, intron_variant		ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.919-2A>G		splice_acceptor_variant, intron_variant			NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00538

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000359 AC: 90 AN: 251010 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00479

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461408 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00539

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000276

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Pendred syndrome Pathogenic:9 Other:1

Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 20, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	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. ​ -
Pathogenic, no assertion criteria provided	clinical testing	The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	May 12, 2020	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Affects, no assertion criteria provided	clinical testing;in vitro	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	Jul 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM3_VeryStrong+PP1_Strong+BS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 17, 2024	- -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 01, 2011

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. -

SLC26A4-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033313; hg19: chr7-107323898;