rs111033308

chr7-107695984-G-Achr7-107695984-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000441.2(SLC26A4):c.1489G>A(p.Gly497Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G497R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1 O:1
• Conservation: PhyloP100: 8.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S26A4_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107695984-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550792.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 7-107695984-G-A is Pathogenic according to our data. Variant chr7-107695984-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43510.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=11, Uncertain_significance=1}. Variant chr7-107695984-G-A is described in Lovd as [Pathogenic]. Variant chr7-107695984-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1489G>A	p.Gly497Ser	missense_variant	13/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1489G>A	p.Gly497Ser	missense_variant	13/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251406 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460894 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 726828

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74240

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000417 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4 Other:1

Affects, no assertion criteria provided	clinical testing;in vitro	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 07, 2021	0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 4, with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). While the p.(Gly497Ser) variant is typically reported in the context of deafness with enlarged vestibular aqueduct (MIM#600791), it cannot be ruled out that individuals with this variant will develop thyroid dysfunction in the future. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many individuals with hearing loss in a homozygous or compound heterozygous state (ClinVar, PMID:28964290, 9500541, 26763877). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	SLC26A4 c.1489G>A, p.G497S alters a residue of SLC26A4 that is previously shown to damage protein function. The variant is homozygous in 3 Palestinian children with pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and is present in 7/282774 alleles on gnomAD, all heterozygotes. -

Pendred syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2022	Variant summary: SLC26A4 c.1489G>A (p.Gly497Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251406 control chromosomes. c.1489G>A has been reported in the literature in multiple individuals affected with sensorineural hearing loss and enlarged vestibular aqueduct, and the variant segregated with disease in affected families (examples: Li_1998, Yazdanpanahi_2015, Abu Rayyan_2020). In functional studies the variant was reported to result in a low level of of pendrin activity (Scott_2000). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, seven classified as pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 497 of the SLC26A4 protein (p.Gly497Ser). This variant is present in population databases (rs111033308, gnomAD 0.005%). This missense change has been observed in individuals with sensorineural hearing loss and enlarged vestibular aqueduct (PMID: 9500541, 26763877, 28964290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43510). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 10861298, 18310264). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Published functional studies demonstrate a damaging effect due to abolishment of complex glycosylation and significant reduction of ion transport activities (Scott et al., 2000; Yoon et al., 2008; Wasano et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34680964, 10861298, 18310264, 27771369, 28964290, 30139988, 31387071, 31599023, 9500541, 26763877, 29546359, 30275481, 34426522, 32747562, 31589614, 33152970, 32645618) -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 23, 2011

The Gly497Ser variant in SLC26A4 has been reported in six probands with Pendred syndrome or sensorineural hearing loss (Scott 2000, Bogazzi 2004, Gardner 2006, Jiang 2010, Li 1998, Pera 2008, Prasad 2004, Yoon 2008). Four of these probands were homozygous or compound heterozygous. Functional studies have shown that the Gly487Ser variant inhibits protein function (Scott 2000, Yoon 2008). In summary , this variant meets our criteria to be classified as pathogenic. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Moderate, PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.99
MPC		0.076
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.92
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033308; hg19: chr7-107336429;