rs111033254

chr7-107698085-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1588T>C(p.Tyr530His) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,609,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y530S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.15

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr7-107698085-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2105136.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-107698085-T-C is Pathogenic according to our data. Variant chr7-107698085-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107698085-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1588T>C	p.Tyr530His	missense_variant	14/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1588T>C	p.Tyr530His	missense_variant	14/21		NM_000441.2	P1
SLC26A4	ENST00000477350.5	n.435T>C		non_coding_transcript_exon_variant	4/5	4
SLC26A4	ENST00000480841.5	n.437T>C		non_coding_transcript_exon_variant	5/8	3
SLC26A4	ENST00000644846.1	c.301T>C	p.Tyr101His	missense_variant, NMD_transcript_variant	4/10

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251182 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135754

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1456946 Hom.: 0 Cov.: 28 AF XY: 0.0000331 AC XY: 24 AN XY: 725130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000424

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000554 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	The c.1588T>C (p.Tyr530His) missense variant in the SLC26A4 gene has been reported as a common deleterious variant associated with Pendred Syndrome (Coyle et al., 1998; Blons et al., 2004). This variant has been reported in several affected individuals, often in trans with a second deleterious variant (V138F, T410M, c.2089+1G>A, V422D, T416P, Y78C, F355S) (Blons et al., 2004; Banghova et al., 2008; Borck et al., 2009; Ladsous et al., 2014). Functional studies have shown this variant affects protein localization within the cell; additionally, some affected individuals harboring this variant have elevated thyroglobulin (Choi et al., 2009; Ladsous et al., 2014). This variant is reported at low frequency within the control population databases (Exome Sequencing Project [ESP] = NA; 1000 Genomes = NA; and ExAC = 0.002). Multiple in silico algorithms predict the variant to have a deleterious effect (GERP = 5.96; CADD = 26.2; PolyPhen = 1; SIFT = 0.02). In addition, reputable diagnostic laboratories have reported this variant as Pathogenic.Therefore, this collective evidence supports the classification of the c.1588T>C (p.Tyr530His) as an autosomal recessive Pathogenic variant for Pendred Syndrome/ Non-syndromic Hearing Loss DFNB4. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2022	Variant summary: SLC26A4 c.1588T>C (p.Tyr530His) results in a conservative amino acid change in the encoded protein sequence. Four 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 251182 control chromosomes. c.1588T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Pendred syndrome (example, Coyle_1998, Borck_2003, Albert_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating an effect on protein trafficking due to retention in the endoplasmic reticulum (ER) (Choi_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 02, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 530 of the SLC26A4 protein (p.Tyr530His). This variant is present in population databases (rs111033254, gnomAD 0.004%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 9618167, 12788906, 19204907, 24224479, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4836). 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: 19204907). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 26, 2015

The p.Tyr530His variant in SLC26A4 has been reported in at least 20 individuals with hearing loss with EVA and/or Mondini dysplasia or with Pendred syndrome (Al bert 2006, Banghova 2008, Blons 2004, Borck 2003, Campbell 2001, Choi 2009, Coyl e 1998, Prasad 2004, Pryor 2005, LMM unpublished data). The variant was compound heterozygous in at least 14 of those probands. This variant was present in 1/6 6632 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs111033254). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a r ecessive carrier frequency. One study has shown that the Tyr530His variant impa cts protein function (Choi 2009). In summary, this variant meets our criteria to be classified as pathogenic (http://personalizedmedicine.partners.org/). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.024	D;.
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.91		Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);
MVP		0.99
MPC		0.075
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.88
gMVP		0.88

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: rs111033254; hg19: chr7-107338530;