rs121908362

chr7-107710132-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000441.2(SLC26A4):c.2168A>G(p.His723Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000653 in 1,609,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H723D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 7.10

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 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107710131-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 949741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-107710132-A-G is Pathogenic according to our data. Variant chr7-107710132-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107710132-A-G is described in Lovd as [Pathogenic]. Variant chr7-107710132-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2168A>G	p.His723Arg	missense_variant	19/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2168A>G	p.His723Arg	missense_variant	19/21		NM_000441.2	P1
SLC26A4	ENST00000644846.1	c.*70A>G		3_prime_UTR_variant, NMD_transcript_variant	8/10
SLC26A4	ENST00000492030.2	n.377-23A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152254 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: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251294 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000659 AC: 96 AN: 1456722 Hom.: 0 Cov.: 28 AF XY: 0.0000662 AC XY: 48 AN XY: 725090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00232

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152372 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74510

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000949 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2022	Variant summary: SLC26A4 c.2168A>G (p.His723Arg) results in a non-conservative amino acid change located in the STAS domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.2168A>G has been reported in the literature in multiple individuals affected with Pendred Syndrome or hearing loss (e.g. Sagong_2012, Jung_2016). These data indicate that the variant is very likely to be associated with disease. Fifteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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	The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	May 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 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 (PMID: 20301640). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 32 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated STAS domain (DECIPHER, Uniprot). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is prevalent in individuals with Asian descent with Pendred syndrome or deafness 4 with enlarged vestibular aqueduct (ClinVar, PMID: 20301640). (SP) 1102 - Strong phenotype match for this individual. (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	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 07, 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	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000441.1(SLC26A4):c.2168A>G(H723R) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18310264, 24007330, 20826203 and 17718863. Classification of NM_000441.1(SLC26A4):c.2168A>G(H723R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:7

Pathogenic, criteria provided, single submitter	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	Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	Jul 01, 2017	- -
Likely 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	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004825, PMID:9618166, PS1_S).A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000949741, PMID:19040761,24599119, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.958, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000113, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2017	The c.2168A>G; p.His723Arg (rs121908362) is one of commonly observed variants reported in patients with Pendred Syndrome and hearing loss across the Asian population (Van Hauwe, 1998; Ishihara, 2010; Sagong, 2013; Asakura, 2010; Li, 2016). Lee (2014) noted that patients with two copies of the p.His723Arg variant had poorer hearing and higher proportion of incomplete cochlear turns (Mondini structures) compared to compound heterozygotes with a single copy and a different SLC26A4 variant. Cell-based and biochemical experiments further demonstrated that p.His723Arg polypeptides are impaired at reaching the plasma membrane and exhibit abnormal ion exchange activity that can be rescued at low temperature (Yoon, 2008). This variant is listed in the Genome Aggregation Database (gnomAD) in the East Asian population at a frequency of 0.16 percent (identified on 31 out of 18,868 chromosomes with 0 homozygotes) and is reported to the ClinVar database as a pathogenic/likely pathogenic variant (Variation ID: 4825). The histidine at position 723 is highly conserved across 12 species (Alamut v2.9.0), and computational analyses of the effects of the p.His723Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether the p.His723Arg variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Published functional studies demonstrate a damaging effect with intracellular retention and decreased protein activity in comparison to wild type (Yoon et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20842945, 19786220, 20583162, 23705809, 25266519, 22884721, 20826203, 23469187, 23755160, 24224479, 9618166, 27176802, 28583500, 27082237, 30693673, 32477112, 31599023, 34943631, 34943614, 11405873, 24007330, 22975760, 11502831, 21961810, 24338212, 26035154, 26100058, 26346818, 27384033, 26763877, 28990112, 28981942, 28786104, 28964290, 27374754, 28802383, 29234782, 28093008, 28052261, 17322586, 30282152, 29447821, 30589569, 30036422, 30733538, 31347505, 30842343, 31564438, 29650690, 31541171, 31827275, 32203226, 30896630, 32425884, 30275481, 32877901, 34170635, 32447495, 15905611, 32459320, 32645618, 32536503, 33597575, 33724713, 34006472, 35204885, 35276235, 35114279, 34801268, 35249537, 34545167, 18310264) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 723 of the SLC26A4 protein (p.His723Arg). This variant is present in population databases (rs121908362, gnomAD 0.2%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11405873, 17322586, 20583162, 22884721, 23705809, 24338212). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4825). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 20583162). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 27, 2019

The p.His723Arg variant in SLC26A4 has been reported in 37 probands with Pendred syndrome (Wu 2005, Van Hauwe 1998, Lee 2008, Asakura 2010, Cho 2006, Dai 2008, Hu 2007, Ishihara 2010, Kim 2009, Park 2003, Reyes 2009, Tsukamoto 2003, Usami 1999, Yoon 2008). Many of these probands were homozygous or compound heterozygous, and the variant has segregated with disease in several families. Furthermore, functional studies revealed that the p.His723Arg variant disrupts the normal cellular localization and ion transport activity of the protein (Yoon 2008, Ishihara 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate. -

SLC26A4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection of the available literature, it has been identified in a homozygous state in 26 patients, in a compound heterozygous state in 67 patients, and in a heterozygous state in 19 patients, including those with Pendred syndrome and autosomal recessive nonsyndromic hearing loss with enlarged vestibular aqueduct (Tsukamoto et al. 2003; Park et al. 2005; Cho et al. 2006; Kim et al. 2009; Reyes et al. 2009; Miyagawa et al. 2014; Lu et al. 2015; Tsukada et al. 2015). Family studies have demonstrated inheritance of the variant from unaffected heterozygous parents. The p.His723Arg variant was identified in a heterozygous state in three of 1024 Asian control alleles (Park et al. 2003; Yuan et al. 2012; Miyagawa et al. 2014) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. Functional studies in HEK 293 and HeLa cells showed the variant causes the protein to be retained in the endoplasmic reticulum rather than localized to the cell membrane and significantly reduces chloride bicarbonate ion exchange function, consistent with the proposed disease mechanism. The defects were rescued by incubation at low temperature, suggesting they may be due to protein misfolding (Yoon et al. 2008). Based on the collective evidence, the p.His723Arg variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.1	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.84
MVP		1.0
MPC		0.076
ClinPred		0.27	T
GERP RS		5.5
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908362; hg19: chr7-107350577;