rs111033242

Positions:

chr7-107675050-C-G

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3PM5PP1_ModeratePP4

This summary comes from the ClinGen Evidence Repository: The c.706C>G variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by valine at amino acid 236 (p.Leu236Val). The variant was identified in 0.01833% (11/59998) of admixed American alleles, which is the highest population minor allele frequency in gnomAD v4.1.0 (PM2_Supporting and BS1 are not met). This variant has been detected in 3 probands in trans with a pathogenic variant, in 5 probands in phase unknown with a pathogenic variant, and in the homozygous state in 3 probands, all of whom had hearing loss and/or inner ear malformations consistent with Pendred syndrome. The variant was also identified with a pathogenic splice site variant in 2 probands (PM3_VeryStrong; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5, ARUP internal data ClinVar SCV000605149.1, Chinese PLA General Hospital internal data, Molecular Otolaryngology and Renal Research Laboratories internal data, Revvity ClinVar SCV002023538.3GeneDx internal data ClinVar SCV001783711.3, Invitae internal data ClinVar SCV002234501.3). This variant was seen in two probands with no second variant identified whose phenotypes were consistent with Pendred syndrome (PMID:34410491, 34515852), as well as in one proband with enlarged vestibular aqueduct who was compound heterozygous with a likely pathogenic variant in phase unknown (PP4; PMID:36703223). A different pathogenic missense variant (p.Leu236Pro) has been previously identified at this codon of SLC26A4, which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 4817). Additionally, the variant was seen in an adult with deafness who had two pathogenic GJB2 variants in trans (Revvity internal data ClinVar SCV002023538.3). The variant has been reported to segregate with hearing loss in two affected family members (PP1_Moderate; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PM5, PP1_Moderate, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA132738/MONDO:0010134/005

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10U:1

Conservation

PhyloP100: 0.128

Variant links:

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]

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 7 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

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 link	c.706C>G	p.Leu236Val	missense_variant	6/21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.706C>G	p.Leu236Val	missense_variant	6/21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251474

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	In silico analysis supports that this variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25991456, 21704276, 31009165, 33885265, 34410491, 31581539, 33924653, 33136026, 30113565, 30268946, 9618166, 9618167, 25999548) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 236 of the SLC26A4 protein (p.Leu236Val). This variant is present in population databases (rs111033242, gnomAD 0.03%). This missense change has been observed in individual(s) with deafness, often in combination with p.Thr67Ser. However, this variant has also been observed without Thr67Ser in affected individual(s) (PMID: 21704276, 25991456; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43565). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Leu236 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618166, 10861298, 12354788, 15689455, 18310264). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Pendred syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 14, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Oct 16, 2024	The c.706C>G variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by valine at amino acid 236 (p.Leu236Val). The variant was identified in 0.01833% (11/59998) of admixed American alleles, which is the highest population minor allele frequency in gnomAD v4.1.0 (PM2_Supporting and BS1 are not met). This variant has been detected in 3 probands in trans with a pathogenic variant, in 5 probands in phase unknown with a pathogenic variant, and in the homozygous state in 3 probands, all of whom had hearing loss and/or inner ear malformations consistent with Pendred syndrome. The variant was also identified with a pathogenic splice site variant in 2 probands (PM3_VeryStrong; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5, ARUP internal data ClinVar SCV000605149.1, Chinese PLA General Hospital internal data, Molecular Otolaryngology and Renal Research Laboratories internal data, Revvity ClinVar SCV002023538.3GeneDx internal data ClinVar SCV001783711.3, Invitae internal data ClinVar SCV002234501.3). This variant was seen in two probands with no second variant identified whose phenotypes were consistent with Pendred syndrome (PMID: 34410491, 34515852), as well as in one proband with enlarged vestibular aqueduct who was compound heterozygous with a likely pathogenic variant in phase unknown (PP4; PMID: 36703223). A different pathogenic missense variant (p.Leu236Pro) has been previously identified at this codon of SLC26A4, which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 4817). Additionally, the variant was seen in an adult with deafness who had two pathogenic GJB2 variants in trans (Revvity internal data ClinVar SCV002023538.3). The variant has been reported to segregate with hearing loss in two affected family members (PP1_Moderate; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PM5, PP1_Moderate, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2024

- -

SLC26A4-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2024

The SLC26A4 c.706C>G variant is predicted to result in the amino acid substitution p.Leu236Val. This variant has been reported in the homozygous state in four unrelated patients with hearing loss and enlarged vestibular aqueduct (EVA) (Chiong et al. 2018. PubMed ID: 30113565). Additionally, a different substitution at this amino acid position is well documented to be pathogenic (p.Leu236Pro; https://www.ncbi.nlm.nih.gov/clinvar/variation/4817/). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/43565/). This variant is interpreted as likely pathogenic. -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 02, 2018

The p.Leu236Val variant in SLC26A4 has been identified 1 heterozygous individual with hearing loss (Chen 2011), 1 heterozygous individual with profound bilatera l hearing loss and multiple congenital anomalies (Tang 2015), in 1 presumed comp ound heterozygous individual with bilateral sensorineural hearing loss (phase no t confirmed; personal communication of ClinVar submitter, ClinVar ID 43565) and in 1 compound heterozygous Asian individual with hearing loss and bilateral temp oral bone abnormalities (LMM data). In the last case, it segregated with disease in the homozygous state in 2 distant relatives (5 meioses removed) with congeni tal hearing loss (LMM data). It has also been identified in 0.03% (9/33580) of L atino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs111033242). This variant also affects a residue that is the site of an established pathogenic variant (p.Leu236Pro; ClinVar ID 4817), su ggesting that changes at this position are not tolerated. Computational predicti on tools and conservation analysis suggest that the p.Leu236Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. It should be noted that this variant is often found in cis with the likely benign p.Thr67Ser variant. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Leu236Val variant is likely pathogenic. ACMG/AMP criteria applied: PM3, PM5, PP1_Moderate, PM2_Su pporting, BP4. -

Deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM2_Supporting, PM3_Strong, PM5, PP1, PP4 -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 22, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

0.050

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.0

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.047

D;.

Sift4G

Benign

0.061

T;.

Polyphen

0.055

B;B

Vest4

0.42

MutPred

0.89

Gain of methylation at K237 (P = 0.0471);Gain of methylation at K237 (P = 0.0471);

MVP

0.93

MPC

0.011

ClinPred

0.050

GERP RS

3.6

Varity_R

0.18

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over