rs397516427

Positions:

chr7-107710109-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3_StrongPS3_SupportingPP4

This summary comes from the ClinGen Evidence Repository: The c.2145G>T variant in SLC26A4 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 715 (p.Lys715Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06777% (95% CI of 29/30610) in the South Asian population (PM2_supporting, BS1, and BA1 not met). This variant has been observed in 3 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3_Strong; PMID:26969326, PMID:32417962, LMM unpublished data SCV000060131.6). At least one proband with this variant presented with clinical features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6).This variant has been observed in several other cases where a second variant in SLC26A4 was not found (PMID:19509082, 19287372, 26188157, 32417962). Functional studies including fluorescence assays and chloride exchange experiments have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19509082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 08/22/23: PM3_Strong, PS3_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261425/MONDO:0010134/005

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8U:2

Conservation

PhyloP100: 0.812

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 Likely_pathogenic. Variant got 6 ACMG points.

PS3

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

PM3

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 linkuse as main transcript	c.2145G>T	p.Lys715Asn	missense_variant	19/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.2145G>T	p.Lys715Asn	missense_variant	19/21		NM_000441.2	ENSP00000494017	P1	O43511-1
SLC26A4	ENST00000644846.1 linkuse as main transcript	c.*47G>T		3_prime_UTR_variant, NMD_transcript_variant	8/10			ENSP00000494344
SLC26A4	ENST00000492030.2 linkuse as main transcript	n.377-46G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

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:

0.000115

AC:

AN:

251292

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135806

show subpopulations

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:

0.000947

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1458468

Hom.:

Cov.:

AF XY:

0.0000703

AC XY:

AN XY:

725890

show subpopulations

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:

0.000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74454

show subpopulations

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

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (PMID:19287372). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 26969326). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 19509082). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.831>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0001154). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 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 lysine to asparagine (exon 19). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (29 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (STAS domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with recessive deafness (ClinVar, Deafnessvariationdatabase, PMID: 19287372, PMID: 26969326, PMID: 25372295). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected Xenopus oocytes demonstrated impaired chloride efflux activity and protein transport (PMID: 19509082) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

Pendred syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	Apr 12, 2021	PS1_Strong, PM2_Supporting, BP4_Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 10, 2018	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Aug 22, 2023	The c.2145G>T variant in SLC26A4 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 715 (p.Lys715Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06777% (95% CI of 29/30610) in the South Asian population (PM2_supporting, BS1, and BA1 not met). This variant has been observed in 3 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3_Strong; PMID: 26969326, PMID: 32417962, LMM unpublished data SCV000060131.6). At least one proband with this variant presented with clinical features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6).This variant has been observed in several other cases where a second variant in SLC26A4 was not found (PMID: 19509082, 19287372, 26188157, 32417962). Functional studies including fluorescence assays and chloride exchange experiments have demonstrated that this variant impacts protein function (PS3_Supporting; PMID: 19509082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 08/22/23: PM3_Strong, PS3_Supporting, PP4. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Reported with a second variant (phase unknown) in unrelated patients with bilateral hearing loss referred for genetic testing at GeneDx and in published literature (Sloan-Heggen et al., 2016); Published functional studies suggest this variant demonstrates reduced anion exchange properties (Dai et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; Classified as uncertain significance by the ClinGen Hearing Loss Variant Curation Expert Panel (VCV000043541.24; Oza et al., 2018); This variant is associated with the following publications: (PMID: 28941661, 19509082, 26188157, 32417962, 18813951, 33614372, 25372295, 35186384, 26186295, 19287372, 25999548, 35249537, 26969326) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -

SLC26A4-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2024

The SLC26A4 c.2145G>T variant is predicted to result in the amino acid substitution p.Lys715Asn. This variant was reported in the compound heterozygous state in an individual with hearing loss as well as in a second individual who also had an enlarged vestibular aqueduct (Table S3, Sloan-Heggen et al. 2015. PubMed ID: 26445815; Chandru et al. 2020. PubMed ID: 32417962). In vitro experiments demonstrated this variant impacts protein function (Dai et al. 2009. PubMed ID: 19509082). This variant is reported in 0.095% of alleles in individuals of South Asian descent in gnomAD and is classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/43541/). 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

Mar 22, 2012

The Lys715Asn variant in SLC26A4 has been reported in a heterozygous state in th ree probands with hearing loss and was absent from 100 control samples (Dia 2009 , Anwar 2009). In addition, functional studies showed reduced Cl- anion exchange activity compared to the wild type (Dia 2009). Furthermore, the presence of thi s variant in combination with a pathogenic variant and in an individual with cli nical features of hearing loss and EVA, increases the likelihood that the Lys715 Asn variant is pathogenic. In summary, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;T

Eigen

Benign

0.0018

Eigen_PC

Benign

0.053

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.57

.;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.080

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.25

T;.

Sift4G

Benign

0.13

T;.

Polyphen

0.022

B;B

Vest4

0.83

MutPred

0.78

Loss of methylation at K715 (P = 0.0126);Loss of methylation at K715 (P = 0.0126);

MVP

0.94

MPC

0.018

ClinPred

0.92

GERP RS

2.7

Varity_R

0.24

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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