rs145254330

chr7-107672182-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1 PM2 PP3 PP5_Very_Strong BP4

The NM_000441.2(SLC26A4):c.349C>T(p.Leu117Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000319 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:3 O:1
• 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 Pathogenic. Variant got 12 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, 5 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 7-107672182-C-T is Pathogenic according to our data. Variant chr7-107672182-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 43555.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-107672182-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.29352403).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.349C>T	p.Leu117Phe	missense_variant	4/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.349C>T	p.Leu117Phe	missense_variant	4/21		NM_000441.2	P1
SLC26A4	ENST00000440056.1	c.349C>T	p.Leu117Phe	missense_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152040 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251428 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000331 AC: 484 AN: 1460958 Hom.: 0 Cov.: 29 AF XY: 0.000336 AC XY: 244 AN XY: 726838

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152160 Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17 AN XY: 74390

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3 Uncertain:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous missense variant was identified, NM_000441.1(SLC26A4):c.349C>T in exon 4 of 21 of the SLC26A4 gene. This substitution is predicted to create a minor amino acid change from a leucine to a phenylalanine at position 117 of the protein; NP_000432.1(SLC26A4):p.(Leu117Phe). The leucine at this position has very high conservation (100 vertebrates, UCSC), and is located within the sulfate transp domain (PDB). In silico software predicts this variant to be damaging (PolyPhen2, MutationAssessor, FATHMM, PROVEAN). The variant is present in the gnomAD population database at a global population frequency of 0.03% (83 heterozygotes, 0 homozygotes) with an Ashkenazi Jewish sub-population frequency of 0.5%. This variant has been previously reported as likely pathogenic in patients with hearing loss (ClinGen Hearing Loss Variant Curation Expert Panel). Functional analysis using human HeLa and HEK cells shows that this variant resulted in normal cellular localisation of the mutant protein and iodide efflux of the cells (Taylor, J. et al. (2002)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -
other, no assertion criteria provided	in vitro;literature only	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	Benign effect in vitro experiment Benign effect in vitro experiment
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Feb 19, 2016	Congenital, profound HL -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Pendred syndrome Pathogenic:3 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Nov 22, 2022	The c.349C>T variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 117. The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel (LMM) (PP4). The variant has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence (BS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VS, PP1_S, PP4, PP3, BS3_P (Hearing Loss VCEP specifications version 2; 11/22/2022). -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Feb 19, 2016	Congenital, profound HL -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2023	Variant summary: SLC26A4 c.349C>T (p.Leu117Phe) 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. The variant allele was found at a frequency of 0.00033 in 251428 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00033 vs 0.0035), allowing no conclusion about variant significance. c.349C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with hearing loss (Dahl_2013, Sloan-Heggen_2016, Brownstein_2020). These data indicate that the variant is very likely to be associated with disease. Two seperate publications have shown the variant behaves similarly to wild-type when expressed in HEK293T/HeLa cells (Taylor_2002, Wasano_2020). Ten ClinVar submitters, including one expert panel, have assessed the variant since 2014: two classified the variant as uncertain significance, five classified the variant as likely pathogenic, three (including the expert panel) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variant reported to segregate with hearing loss in two unrelated families of Ashkenazi Jewish background (SCV000282016.1, SCV000282017.1; ClinVar); This variant is associated with the following publications: (PMID: 19608655, 25262649, 27771369, 11932316, 16570074, 10700480, 31589614, 26969326, 31599023, 36147510, 30245029, 14508505, 34410491, 16950989, 33111345, 30311386, 33879512, 36233414, 37108562) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 117 of the SLC26A4 protein (p.Leu117Phe). This variant is present in population databases (rs145254330, gnomAD 0.5%). This missense change has been observed in individuals with profound congenital deafness (PMID: 23555729, 26969326, 33111345, 34410491). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43555). 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 does not substantially affect SLC26A4 function (PMID: 11932316, 31599023, 32165640). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 08, 2020

The p.Leu117Phe variant in SLC26A4 has been previously reported in 8 individuals with hearing loss, 6 of whom had enlarged vestibular aqueducts, and 5 of whom had a second SLC26A4 variant on the remaining allele (Reardon 2000, Albert 2006, Sloan-Heggen 2016, ClinVar SCV000282015.1, LMM unpublished data). This variant was classified as Likely Pathogenic on Sep 26, 2018 by the ClinGen-approved Hearing Loss expert panel (Variation ID 43555). This variant has also been reported in the homozygous state in 2 Ashkenazi Jewish families with hearing loss (Brownstein 2020, bioRxiv 2020.06.11.144790; doi: https://doi.org/10.1101/2020.06.11.144790). The variant segregated in 2 affected family members; however, one affected individual was heterozygous only for the variant. This variant is also present in 0.5% (54/10368) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145254330). However, given the lack of understanding of Pendred syndrome prevalence in the Ashkenazi Jewish population, this allele frequency was not considered strong enough conflicting evidence to counter the pathogenic evidence. Two in vitro functional study demonstrated that the variant did not impact localization of the protein to the cell membrane or iodide efflux capacity; however, not all ion transport functions of the mutant proteins were assessed (Taylor 2002, Wasano 2020). In addition, the leucine (Leu) residue at position 117 is highly conserved across mammals and distant species, suggesting that variants at this position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP criteria applied: PM3_VeryStrong, PP1, PP4, PP3, BS1, BS3_Supporting. -

SLC26A4-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The SLC26A4 c.349C>T variant is predicted to result in the amino acid substitution p.Leu117Phe. This variant has been reported along with a second causal variant in a patient with hearing loss (Table S3, Sloan-Heggen et al 2016. PubMed ID: 26969326) and in three patients in which a second causal variant was not identified (Reardon et al 2000. PubMed ID: 10700480; Taylor et al 2002. PubMed ID: 11932316; Albert et al 2006. PubMed ID: 16570074). This variant has also been reported in the homozygous state in four patients with hearing loss from two families, being heterozygous in four unaffected and one affected individual (Figure S1, Brownstein et al 2020. PubMed ID: 33111345). A functional study found this variant had iodide efflux levels similar to wildtype (Taylor et al 2002. PubMed ID: 11932316). This variant is reported in 0.52% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is classified as likely pathogenic for autosomal recessive Pendred syndrome by the ClinGen Hearing Loss Variant Curation Expert Panel, in part based on internal data from other clinical testing laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/43555/). This variant is interpreted as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 19, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2018

The p.Leu117Phe variant (rs145254330) has been reported in multiple individuals with non-syndromic hearing loss (Reardon 2000, Albert 2006, Sloan-Heggen 2016); however, it has never been observed in trans with any pathogenic allele, and functional studies revealed no difference in protein localization or channel function when compared to wild-type SLC26A4 protein (Taylor 2002). Furthermore, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.51% (identified in 52 out of 10,150 chromosomes), and is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 43555). Taken together, the clinical significance of the p.Leu117Phe variant cannot be determined with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.91
MVP		0.98
MPC		0.075
ClinPred		0.39	T
GERP RS		5.1
Varity_R		0.92
gMVP		0.82

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: rs145254330; hg19: chr7-107312627; COSMIC: COSV55915432;