rs111033256

chr7-107675060-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000441.2(SLC26A4):c.716T>A(p.Val239Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000954 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:25 U:1 O:2
• Conservation: PhyloP100: 4.50

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 7-107675060-T-A is Pathogenic according to our data. Variant chr7-107675060-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43566.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=18, not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr7-107675060-T-A is described in Lovd as [Pathogenic]. Variant chr7-107675060-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.716T>A	p.Val239Asp	missense_variant	6/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.716T>A	p.Val239Asp	missense_variant	6/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151978 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251468 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152096 Hom.: 0 Cov.: 30 AF XY: 0.0000807 AC XY: 6 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:25 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2020	Variant summary: SLC26A4 c.716T>A (p.Val239Asp) results in a non-conservative amino acid change located in the SLC26A/SulP transporter 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 0.0002 in 251468 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred syndrome (0.0002 vs 0.0035). c.716T>A has been reported in the literature in numerous individuals affected with Pendred syndrome (eg. Khan_2013, Dossena_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic retuclum, and impaired protein function (Walsh_2006, Dossena_2011). Four 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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	Severe to Profound SNHL -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.716T>A (p.Val239Asp) in SLC26A4 gene has been observed in several individuals and families affected with SLC26A4-related conditions (Tekin M et.al.,2003). Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic retuclum, and impaired protein function (Walsh T et.al.,2006). This variant has been reported to the ClinVar database as Pathogenic. The p.Val239Asp variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.02028 % is reported in gnomAD. The amino acid Val at position 239 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val239Asp in SLC26A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:6 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to aspartic acid (exon 6). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (51 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (sulfate permease family domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; Khan, M. et al . (2013)). (P) 1002 - Moderate functional evidence supporting abnormal protein function (Dossena, S. et al. (2011); Walsh, T. et al. (2006)). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	SLC26A4 c.716T>A, p.V239D has been shown to decrease SLC26A4 ion transport activity (PMID: 22116360). The variant is homozygous in 10 Palestinian children from a single kindred with pre-lingual hearing loss (Abu Rayyan 2020). It is present in 1 of 1300 Palestinian controls, as a heterozygote, and present in 51/251468 alleles on gnomAD, all heterozygotes. -
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: VCV000043566, PMID:12676893, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 12676893, 23504402, 30303587, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 31599023, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.935, 3CNET: 0.981, 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: 0.000203, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.716T>A (p.Val239Asp) in the SLC26A4 gene has been reported previously in homozygous state in individuals affected with hearing loss. Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic reticulum, and impaired protein function (Walsh et al., 2006; Dossena et al., 2011). This variant is reported with the allele frequency (0.02%) in the gnomAD and novel (not in any individuals) in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/Pathogenic (Multiple submission). The amino acid Valine at position 239 is changed to an Aspartic Acid changing the protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Val239Asp in SLC26A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	UAEU Genomics Laboratory, United Arab Emirates University	Nov 22, 2021	The missense variant NM_000441.2(SLC26A4):c.716T>A (p.Val239Asp) has been observed in several individuals and families affected with SLC26A4-related conditions (PMID: 12974744, 16460646, 23770805, 25394566). The Val239Asp is a common variant in the SLC26A4 gene that is associated with Pendred syndrome in the Pakistani population (PMID:19287372). This variant is observed in 51/30616 (0.1666%) alleles from individuals of gnomAD South Asian background in the gnomAD dataset (Genome Aggregation Database et al., 2020), but was not seen in the homozygous state. Computational prediction tools and conservational analysis predict that the p.Val239Asp missense change has a damaging effect on the protein structure or function. Experimental studies have shown that this missense change has a deleterious effect on protein function and localization (PMID: 16460646, 22116360) For these reasons, this variant has been classified as Pathogenic. -
Affects, no assertion criteria provided	in vitro;literature only	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	Common variant accounting for approximately 30% of the mutant alleles of SLC26A4; suggested to be a founder variant in the Pakistani population (Anwar et al., 2009); Published functional studies demonstrate that this variant reduces anion transport activity, affects protein localization and overall severely impairs normal protein function (Park et al., 2003; Dossena et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27771369, 23965030, 33879512, 25394566, 16460646, 12676893, 12974744, 23336812, 30077349, 23504402, 31389194, 30303587, 23770805, 31599023, 32417962, 34171171, 33231815, 32747562, 33199029, 22116360, 19287372) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 239 of the SLC26A4 protein (p.Val239Asp). This variant is present in population databases (rs111033256, gnomAD 0.2%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 12974744, 16460646, 23770805, 25394566). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43566). 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 have shown that this missense change affects SLC26A4 function (PMID: 16460646, 22116360). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 28, 2021	PS3, PM3_strong, PP1, PP3, PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 06, 2021	- -

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

Jun 30, 2022

The p.Val239Asp variant in SLC26A4 has been reported in >20 homozygous or compound heterozygous individuals with hearing loss or Pendred syndrome and segregated with disease in at least 10 affected individuals from multiple families (Tekin 2003 PMID: 12974744, Park 2003 PMID: 12676893, Walsh 2005 PMID: 16460646, Anwar 2009 PMID: 19287372, Soh 2015 PMID: 25394566). It has also been identified in 0.14% (7/4828) of South Asian chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org), however this variant is thought to be a founder mutation in this population (Anwar 2009 PMID: 19287372). This variant has also been reported in ClinVar (Variation ID 43566). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function and have shown that protein trafficking is affected and iodide trasport activity is reduced (Walsh 2005 PMID: 16460646, Dossena 2011 PMID: 22116360, Wassano 2020 PMID: 19287372). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred Syndrome. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Moderate, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.84	P;P
Vest4		0.96
MutPred		0.94		Loss of stability (P = 0.0337);Loss of stability (P = 0.0337);
MVP		0.98
MPC		0.056
ClinPred		0.28	T
GERP RS		5.6
Varity_R		0.97
gMVP		0.98

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: rs111033256; hg19: chr7-107315505;