rs111033257

Variant names:

• chr7-107700162-G-A
• rs111033257
• NM_000441.2:c.1694G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM3_Strong PS3_Supporting PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1694G>A variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 565 (p.Cys565Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15418) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold ≤0.00007 (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). Radio isotope assays in Xenopus oocytes and HEK293T cell lines demonstrated that cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin indicating that this variant impacts protein function (PS3_Supporting; PMID:19204907, 31599023).This variant has been detected in at least 4 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aqueduct (total of 3.5 PM3 points, PM3_Strong). One individual with Pendred syndrome was compound heterozygous with a pathogenic variant p.Q514R (ClinVar ID 43511, PMID:19204907, 15689455). The second individual was a Pendred syndrome patient compound heterozygous with a pathogenic variant p.L236P (ClinVar ID 4817, PMID:9618166). The third individual had nonsyndromic hearing loss with enlarged vestibular aqueduct which is highly specific for Pendred syndrome and was compound heterozygous with pathogenic p.H723R (ClinVar ID 4825, PMID:14508505, PP4). The fourth individual had sensorineural hearing loss and enlarged vestibular aqueduct and was assumed compound heterozygous with pathogenic c.1342-2_1343dupAGTC (p.Leu450Glyfs*19) but phase unknown (Internal data from LMM). In summary, this variant has been classified as likely pathogenic for AR Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PS3_Supporting, PM3_Strong, PP4. (VCEP specifications version 2; 07.19.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA261418/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 2.97
• Publications: 21 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1694G>A	p.Cys565Tyr	missense	Exon 15 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1694G>A	p.Cys565Tyr	missense	Exon 15 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1694G>A	p.Cys565Tyr	missense	Exon 14 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1616G>A	p.Cys539Tyr	missense	Exon 14 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000938 AC: 13 AN: 1386592 Hom.: 0 Cov.: 23 AF XY: 0.00000432 AC XY: 3 AN XY: 694518

African (AFR) AF: 0.00 AC: 0 AN: 31962

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 84764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.0000115 AC: 12 AN: 1043398

Other (OTH) AF: 0.0000173 AC: 1 AN: 57840

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000408 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Pendred syndrome (4)
2	-	-	not provided (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 4 (2)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.6	L
PhyloP100		3.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.055	T
Polyphen		0.59	P
Vest4		0.45
MVP		0.98
MPC		0.021
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.46
gMVP		0.71
Mutation Taster		=2/98	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: rs111033257; hg19: chr7-107340607;