rs111033242

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 đť‘“: 0.000016 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

8
11

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]

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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
SLC26A4NM_000441.2 linkc.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
SLC26A4ENST00000644269.2 linkc.706C>G p.Leu236Val missense_variant 6/21 NM_000441.2 ENSP00000494017.1 O43511-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251474
Hom.:
0
AF XY:
0.0000368
AC XY:
5
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:
24
AN:
1461812
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
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.:
30
Bravo
AF:
0.0000227
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingRevvity Omics, RevvityMar 02, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 04, 2022In 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This 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 submitterclinical testingCounsylJul 14, 2016- -
Pathogenic, reviewed by expert panelcurationClinGen Hearing Loss Variant Curation Expert PanelOct 16, 2024The 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 submitterclinical testingBaylor GeneticsMar 16, 2024- -
SLC26A4-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 08, 2024The 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 02, 2018The 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 submitterresearchAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalOct 04, 2024PM2_Supporting, PM3_Strong, PM5, PP1, PP4 -
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 22, 2024- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 09, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
D;D
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.10
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.86
.;D
M_CAP
Benign
0.084
D
MetaRNN
Uncertain
0.55
D;D
MetaSVM
Uncertain
0.050
D
MutationAssessor
Benign
1.1
L;L
PrimateAI
Uncertain
0.69
T
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
T
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.

Other links and lift over

dbSNP: rs111033242; hg19: chr7-107315495; API