rs111033244

chr7-107690125-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1151A>G(p.Glu384Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 1,577,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E384E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.7957
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 8.26

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 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-107690125-A-G is Pathogenic according to our data. Variant chr7-107690125-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107690125-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1151A>G	p.Glu384Gly	missense_variant, splice_region_variant	10/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1151A>G	p.Glu384Gly	missense_variant, splice_region_variant	10/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 251090 Hom.: 0 AF XY: 0.000140 AC XY: 19 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: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000373 AC: 532 AN: 1425244 Hom.: 0 Cov.: 27 AF XY: 0.000360 AC XY: 256 AN XY: 711362

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000480

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74328

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2022	Variant summary: SLC26A4 c.1151A>G (p.Glu384Gly) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251090 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.1151A>G has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with features of Pendred Syndrome/Syndromic Sensorineural Hearing Loss (SNHL)/Non-syndromic SNHL (example, Coyle_1998, Hutchin_2005, Molina-Ramirez_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of Pendrin induced chloride and iodide transport (Scott_2000) and complete retention of Pendrin in the endoplasmic reticulum (ER) as a major mechanism for Pendred syndrome (Rotman-Pikielny_2002). Eight 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	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2019	NM_000441.1(SLC26A4):c.1151A>G(E384G) is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 15689455, 9618167, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.1151A>G(E384G) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 384 of the SLC26A4 protein (p.Glu384Gly). This variant is present in population databases (rs111033244, gnomAD 0.02%). This missense change has been observed in individuals with Pendred syndrome or nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 9618167, 15355436, 15689455, 16283880, 24224479). ClinVar contains an entry for this variant (Variation ID: 4820). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 10861298, 12354788, 18310264, 22116358). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2023	Published functional studies demonstrate a damaging effect due to aberrant protein processing, with retention of pendrin in the endoplasmic reticulum and absence of proper pendrin assembly at the cell membrane as well as impaired protein glycosylation (Scott et al., 2000; Yoon et al., 2008; Rotman-Pikielny et al., 2002); 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: 14508505, 21455268, 26485571, 11317356, 14679580, 20553101, 24224479, 19620588, 34416374, 31589614, 32853555, 33879512, 31980526, 22975760, 10861298, 12354788, 18310264, 24860705, 23824432, 19017801, 25290043, 18368581, 18250610, 15368487, 25455162, 22116358, 20739942, 9604973, 9618167, 23336812, 15355436, 12788906, 21917135, 17672986, 23838540, 20621367, 23504402, 23965030, 15689455, 19204907, 11919333, 16283880, 15099345, 19509082, 20301640, 27771369, 34171171) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2022	PP3, PM2_supporting, PM3_very_strong, PS3 -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The SLC26A4 c.1151A>G (p.E384G) variant has been previously reported in multiple individuals with Pendred syndrome or DFNB4 nonsyndromic hearing loss (PMID: 9618167; 15355436; 10861298; 15689455; 16283880; 24224479). -
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 glutamic acid to glycine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (30 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 transporter domain; PDB, NCBI). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in patients with hearing loss with enlarged vestibular aqueduct or Pendred syndrome (ClinVar, PMIDs: 26485571, 19204907, 9618167). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies showed the mutant protein was retained in the endoplasmic reticulum in human COS7 cells (PMID:12354788). The iodide and chloride uptake was lost in Xenopus oocytes containing the mutant cRNA. (PMID:10861298). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

SLC26A4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 24, 2018

Across a selection of the available literature, the SLC26A4 c.1151A>G (p.Glu384Gly) missense variant has been identified in at least 24 probands with Pendred syndrome or non-syndromic hearing loss, with 16 probands in a compound heterozygous state (with two sib-pairs) and eight probands in a heterozygous state (Coyle et al. 1998; Borck et al. 2003; Blons et al. 2004; Hutchin et al. 2005; Pryor et al. 2005; Dai et al. 2009; Choi et al. 2009; Jonard et al. 2010). Segregation with disease was found in at least one family (Borck et al. 2003). The variant was absent from 415 controls and is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies have shown that the p.Glu384Gly variant protein is consistently located in the intracellular region rather than the plasma membrane and shows decreased Cl-/HCO3- exchange activity (Rotman-Pikielny et al. 2002; Yoon et al. 2008) and an almost complete loss of pendrin-induced iodide and chloride transport activity compared to wild type (Scott et al. 2000; Choi et al. 2009). Based on the collective evidence, the p.Glu384Gly 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. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 16, 2020

The p.Glu384Gly variant in SLC26A4 has been reported in at least 20 probands with Pendred syndrome or sensorineural hearing loss and segregated in additional affected relatives (Jonard 2010 PMID: 20621367, Coyle 1998 PMID: 9618167, Scott 2000 PMID: 10861298, Dai 2009 PMID: 19509082, Rotman-Pikielny 2002 PMID: 12354788, Borck 2003 PMID: 12788906, Blons 2004 PMID: 15355436, Choi 2009 PMID: 19204907, Cremers 1998 PMID: 9604973, Hutchin 2005 PMID: 16283880, Prasad 2004 PMID: 14679580, Pryor 2005 PMID: 15689455, Shears 2004 PMID: 15099345, Yoon 2008 PMID: 18310264, LMM data). Many of these probands were homozygous or compound heterozygous. It has been identified in 0.022% (28/126362) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033244). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies have shown that the p.Glu384Gly variant protein confers no iodide and chloride transport activity (Scott 2000 PMID: 10861298, Choi 2009 PMID: 19204907). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss or Pendred syndrome based on biallelic occurrences in multiple affected individuals, segregation studies, low frequency in the general population, and functional evidence. ACMG/AMP criteria applied: PM3_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP1, PP4. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		1.0
MVP		1.0
MPC		0.076
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
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: rs111033244; hg19: chr7-107330570;