7-107690236-A-G

Variant names:

• chr7-107690236-A-G
• rs201660407
• NM_000441.2:c.1262A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM5 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1262A>G variant in SLC26A4 is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 421 (p.Gln421Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/113084) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). Another missense variant, c.1262A>C (p.Gln421Pro), at the same codon has been classified as likely pathogenic for autosomal recessive Pendred syndrome (PM5; PMID:17718863, 23918157, 24224479, 28964290). The p.Gln421Arg variant has been reported in five individuals with hearing loss and inner ear abnormalities, which is highly specific for Pendred syndrome (PP4). Two individuals did not have a variant on the second allele identified (PMIDs: 23965030, 14679580). Two individuals were compound heterozygous for the CEVA haplotype, and one individual was compound heterozygous for a variant of uncertain significance, c.284G>A p.Gly95Glu. Phase for these individuals was unknown (0 PM3 points, PMID:36833263). This variant was re-reviewed on 6.27.2023, and PM2 was downgraded to PM2_Supporting following the most recent specification criteria. Because no contradictory evidence was added, this variant was retained at likely pathogenic for autosomal recessive Pendrome syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM5, PM2_Supporting, PP3, PP4. (VCEP specifications version 2; 06.21.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA4432734/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:3
• Conservation: PhyloP100: 8.16
• 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

ENSG00000300331 (HGNC:):

ACMG classification

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1262A>G	p.Gln421Arg	missense_variant, splice_region_variant	Exon 10 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1262A>G	p.Gln421Arg	missense_variant, splice_region_variant	Exon 10 of 21		NM_000441.2	ENSP00000494017.1
ENSG00000300331	ENST00000771044.1	n.187-16T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250686 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000122 AC: 17 AN: 1398330 Hom.: 0 Cov.: 24 AF XY: 0.0000114 AC XY: 8 AN XY: 699612

African (AFR) AF: 0.00 AC: 0 AN: 32224

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 85034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.0000161 AC: 17 AN: 1054090

Other (OTH) AF: 0.00 AC: 0 AN: 58294

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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: 0.0000163 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Pendred syndrome Pathogenic:2 Uncertain:3

Mar 07, 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.

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC26A4 c.1262A>G (p.Gln421Arg) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions could not be confirmed experimentally where the variant was determined to exhibit wild-type splice form (Lee_2019). The variant allele was found at a frequency of 1.2e-05 in 250686 control chromosomes (gnomAD). c.1262A>G has been reported in the literature in a study of individuals with clinical diagnosis of dilated vestibular aqueduct or Mondini dysplasia (Prasad_2004). Other variants affecting the same amino acid residue (p.Q421L, p.Q421K, p.Q421P) have been cited in ClinVar and HGMD as pathogenic and disease-associated. These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) (evaluation after 2014) cite the variant as likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jun 21, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1262A>G variant in SLC26A4 is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 421 (p.Gln421Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/113084) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). Another missense variant, c.1262A>C (p.Gln421Pro), at the same codon has been classified as likely pathogenic for autosomal recessive Pendred syndrome (PM5; PMID: 17718863, 23918157, 24224479, 28964290). The p.Gln421Arg variant has been reported in five individuals with hearing loss and inner ear abnormalities, which is highly specific for Pendred syndrome (PP4). Two individuals did not have a variant on the second allele identified (PMIDs: 23965030, 14679580). Two individuals were compound heterozygous for the CEVA haplotype, and one individual was compound heterozygous for a variant of uncertain significance, c.284G>A p.Gly95Glu. Phase for these individuals was unknown (0 PM3 points, PMID: 36833263). This variant was re-reviewed on 6.27.2023, and PM2 was downgraded to PM2_Supporting following the most recent specification criteria. Because no contradictory evidence was added, this variant was retained at likely pathogenic for autosomal recessive Pendrome syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM5, PM2_Supporting, PP3, PP4. (VCEP specifications version 2; 06.21.2023).

May 07, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2

Mar 14, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 10, 2022

The Shared Resource Centre "Genome", Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Dec 11, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q421R variant in the SLC26A4 gene has been reported as a single heterozygous variant in an individual with hearing loss (Landa et al., 2013). It was also identified in another individual with a reported clinical diagnosis of Pendred syndrome; it was not specified whether this individual harbored a second SLC26A4 variant (Prasad et al., 2004). The Q421R variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q421R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Other missense variants at the same residue (Q421K, Q421P, Q421L) and missense variants nearby residues (T420I, V422I, V422D, G424D, I426N ) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, we classify this variant as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.0	.;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.0	M;M
PhyloP100		8.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Vest4		0.97
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.89
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201660407; hg19: chr7-107330681;