NM_000441.2:c.554G>C

Variant names:

• chr7-107674302-G-C
• rs542620119
• NM_000441.2:c.554G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3_Supporting PM3 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.554G>A variant in SLC26A4 is a missense variant predicted to cause substitution of arginine by threonine at amino acid 185 (p.Arg185Thr). The variant was present in 0.0165% (1/6062) of Middle Eastern alleles, which is the highest population minor allele frequency in gnomAD v4.1.0, and PM2_Supporting was applied at the recommendation of the expert panel. This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as in three probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID:24051746, 20597900, 22285650, 34680964). The variant was also observed in one proband with limited phenotype information and no second variant identified (PMID:31387071). Additionally, it was observed in one proband with hearing loss, enlarged vestibular aqueduct, and Mondini malformation who was compound heterozygous with a second pathogenic variant with phase unknown (PMID:34599368). The variant was also seen in an infant with mild congenital bilateral sensorineural hearing loss who also had two pathogenic OTOG variants in trans (Invitae internal data ClinVar SCV002243689.3). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID:22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3, PS3_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274070/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 9.44
• Publications: 5 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

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 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.
• PP3: 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.554G>C	p.Arg185Thr	missense	Exon 5 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.554G>C	p.Arg185Thr	missense	Exon 5 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.554G>C	p.Arg185Thr	missense	Exon 4 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.554G>C	p.Arg185Thr	missense	Exon 5 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152152 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251456 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35 AN XY: 727172

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111844

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.075
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.89
Mutation Taster		=11/89	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: rs542620119; hg19: chr7-107314747;