rs397516424

Variant names:

• chr7-107701986-A-G
• rs397516424
• NM_000441.2:c.1963A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PM3 PP1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID:26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID:26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. 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 8/22/2023 (PM2_Supporting, PP4, PM3, PP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA261421/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:3
• Conservation: PhyloP100: 3.78
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 17 of 21	NP_000432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 17 of 21	ENSP00000494017.1
	SLC26A4	ENST00000492030.2	TSL:5	n.250A>G		non_coding_transcript_exon	Exon 2 of 6
	SLC26A4	ENST00000644846.1		n.673A>G		non_coding_transcript_exon	Exon 7 of 10	ENSP00000494344.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251192 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111956

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00000920 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 655 of the SLC26A4 protein (p.Ile655Val). This variant is present in population databases (rs397516424, gnomAD 0.006%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 26894580, 36703223). ClinVar contains an entry for this variant (Variation ID: 43528). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Dec 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26894580, 36703223, 37811145)

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC26A4: PM3:Strong, PM2, PP4, BP4

Pendred syndrome Pathogenic:1 Uncertain:1

Aug 27, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID: 26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID: 26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. 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 8/22/2023 (PM2_Supporting, PP4, PM3, PP1)

Apr 19, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Jan 05, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rare genetic deafness Pathogenic:1

Feb 06, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Deafness Pathogenic:1

Oct 04, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PM1, PM3, PP1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.24
Sift	Benign	0.48	T
Sift4G	Benign	0.27	T
Polyphen		0.025	B
Vest4		0.23
MVP		0.87
MPC		0.012
ClinPred		0.085	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.53
Mutation Taster		=67/33	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516424; hg19: chr7-107342431;