rs111033242

Variant names:

• chr7-107675050-C-G
• rs111033242
• NM_000441.2:c.706C>G

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP1_Moderate PM5 PP4 PM3

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 𝑓: 0.000016 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:1
• Conservation: PhyloP100: 0.128
• Publications: 12 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: Pathogenic. The variant received 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.

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.706C>G	p.Leu236Val	missense	Exon 6 of 21	NP_000432.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.706C>G	p.Leu236Val	missense	Exon 6 of 21	ENSP00000494017.1
	SLC26A4	ENST00000888701.1		c.706C>G	p.Leu236Val	missense	Exon 5 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.706C>G	p.Leu236Val	missense	Exon 6 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251474 AF XY: 0.0000368

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111938

Other (OTH) AF: 0.000166 AC: 10 AN: 60392

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Pendred syndrome (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	Deafness (1)
-	1	-	not specified (1)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	Rare genetic deafness (1)
1	-	-	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.050	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.13
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
Vest4		0.42
MutPred		0.89		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
Mutation Taster		=65/35	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033242; hg19: chr7-107315495;