rs397516421

chr7-107701101-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1708G>A(p.Val570Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000321 in 1,586,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V570A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:2
• Conservation: PhyloP100: 7.68

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-107701101-G-A is Pathogenic according to our data. Variant chr7-107701101-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43521.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1708G>A	p.Val570Ile	missense_variant, splice_region_variant	16/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1708G>A	p.Val570Ile	missense_variant, splice_region_variant	16/21		NM_000441.2	P1
SLC26A4	ENST00000480841.5	n.557G>A		splice_region_variant, non_coding_transcript_exon_variant	7/8	3
SLC26A4	ENST00000644846.1	c.421G>A	p.Val141Ile	missense_variant, splice_region_variant, NMD_transcript_variant	6/10
SLC26A4	ENST00000492030.2	n.91-726G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

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

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251016 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000300 AC: 43 AN: 1434714 Hom.: 0 Cov.: 26 AF XY: 0.0000419 AC XY: 30 AN XY: 715664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000120

Gnomad4 OTH exome AF: 0.0000505

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2022	In silico analysis supports that this missense variant does not alter protein structure/function.; Classified as likely pathogenic by the ClinGen Hearing Loss Expert Panel (ClinVar SCV001164268.1; Oza et al., 2018); This variant is associated with the following publications: (PMID: 34230634, 30311386, 34170635) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 570 of the SLC26A4 protein (p.Val570Ile). This variant is present in population databases (rs397516421, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome and/or deafness (PMID: 34170635; Invitae; ClinVar entry for Variation ID: 43521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43521). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Pendred syndrome Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Mar 30, 2018	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Oct 31, 2022	The c.1708G>A variant in SLC26A4 is a missense variant predicted to cause the substitution of valine by isoleucine at amino acid 570 (p.Val570Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computations predictor REVEL gives a score of 0.547, which is neither above nor below the thresholds predicting a damaging or benign impact on SLC26A4 function. This variant is located at the first nucleotide of the exon and is heavily conserved in UCSC. Splice prediction analysis using MaxEntScan suggests an impact on splicing from the loss of the 3' consensus splice sequence (PP3). The c.1708G>A (p.Val570Ile) variant in SLC26A4 has also been detected in 3 different patients with hearing loss and the variant was found in trans with the pathogenic variant p.Leu117Phe.This variant has been detected in at least 3 individuals with Pendred syndrome. All of these individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (3 PM3 points, PMID: 34170635, SCV000060111.6) (PM3_Strong). At least two probands with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PMID: 34170635, SCV000060111.6) (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022) -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 07, 2023

- -

SLC26A4-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2022

The SLC26A4 c.1708G>A variant is predicted to result in the amino acid substitution p.Val570Ile. This variant was reported along with a second pathogenic variant in a patient with hearing loss and enlarged vestibular aqueduct (Tian et al 2021. PubMed ID: 34170635). This variant is reported in 0.080% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107341546-G-A). This variant is classified as likely pathogenic for autosomal recessive Pendred syndrome by the ClinGen Hearing Loss Variant Curation Expert Panel, in part based on internal data from other clinical testing laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/43521/). We interpret this variant as likely pathogenic. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 01, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val570Ile variant in SLC26A4 has been identified by our laboratory in two Ashkenazi Jewis h individuals with hearing loss and EVA who also carried a second SLC26A4 varian t of uncertain clinical significance and one individual with hearing loss and Mo ndini dysplasia who did not carry a second pathogenic variant in the SLC26A4 gen e. Moreover, this variant has been identified in one other proband as reported o n the MORL website (www.healthcare.uiowa.edu/labs/pendredandbor/slcMutations.htm ), but was absent from large population studies. The valine (Val) residue at pos ition 570 is highly conserved across species. In addition, the G nucleotide at p osition 1708 is located within the 3? splice junction consensus sequence and the refore could impact splicing (in silico programs suggest a modest divergence fro m consensus). In summary, the clinical significance of the p.Val570Ile variant i s uncertain; however the available data suggest that it is more likely to be pat hogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.85	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.082	T;.
Sift4G	Benign	0.14	T;.
Polyphen		0.97	D;D
Vest4		0.62
MutPred		0.50		Gain of catalytic residue at V570 (P = 0.0182);Gain of catalytic residue at V570 (P = 0.0182);
MVP		0.99
MPC		0.076
ClinPred		0.42	T
GERP RS		5.7
Varity_R		0.35
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.080		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: rs397516421; hg19: chr7-107341546;