rs768471577

Variant names:

• chr7-107694476-A-G
• rs768471577
• NM_000441.2:c.1337A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1337A>G​(p.Gln446Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,612,178 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.29

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

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000441.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 7-107694476-A-G is Pathogenic according to our data. Variant chr7-107694476-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1337A>G	p.Gln446Arg	missense_variant	Exon 11 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1337A>G	p.Gln446Arg	missense_variant	Exon 11 of 21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152188 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: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000758 AC: 19 AN: 250738 AF XY: 0.000103

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1459990 Hom.: 0 Cov.: 30 AF XY: 0.0000578 AC XY: 42 AN XY: 726406

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33424

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44688

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26112

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39688

Gnomad4 SAS exome AF: 0.000638 AC: 55 AN: 86234

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53402

Gnomad4 NFE exome AF: 9.01e-7 AC: 1 AN: 1110374

Gnomad4 Remaining exome AF: 0.0000332 AC: 2 AN: 60304

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000621375 AN: 0.000621375

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3

Dec 03, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550505, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11932316, PS3_S).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000076, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.914, 3CNET: 0.817, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 23, 2022

UAEU Genomics Laboratory, United Arab Emirates University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The missense variant NM_000441.2(SLC26A4):c.1337A>G (p.Gln446Arg) has been reported in homozygous state in several families affected with hearing loss (PMID: 30303587, PMID: 19287372, PMID: 24949729). This variant is observed in 18/30616 (0.06%) alleles from individuals of South Asian background in the gnomAD database, but was not seen in the homozygous state. Computational prediction tools and conservation analysis indicate that this change is damaging to the protein. Published in vitro functional studies indicated that this variant leads to mis-localization of the protein and loss of pendrin iodide transport (PMID: 11932316). This variant has been confirmed to occur in trans (in a compound heterozygous state) with a second variant in the patient and his sibling. For these reasons, this variant has been classified as Pathogenic. -

Pendred syndrome Pathogenic:2

Feb 02, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC26A4 c.1337A>G (p.Gln446Arg) 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. The variant allele was found at a frequency of 7.6e-05 in 250738 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00059 vs 0.0035), allowing no conclusion about variant significance. c.1337A>G has been reported in the literature in the homozygous or compound heterozygous state in multiple families affected with hearing loss (e.g. Taylor_2002, Rehman_2015, Naz_2017, Richard_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant failed to reach the cell membrane and colocalized with the endoplasmic reticulum, and had lost its ability to transport iodide (Taylor_2002). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 09, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316). 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. ClinVar contains an entry for this variant (Variation ID: 550505). This missense change has been observed in individuals with Pendred syndrome or non-syndromic deafness (PMID: 11932316, 19287372, 24949729, 25394566, 25491636, 27573290). This variant is present in population databases (rs768471577, gnomAD 0.06%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 446 of the SLC26A4 protein (p.Gln446Arg). -

Hearing loss, autosomal recessive Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.91
Sift	Benign	0.24	T;.
Sift4G	Uncertain	0.052	T;.
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.95		Loss of ubiquitination at K447 (P = 0.1154);Loss of ubiquitination at K447 (P = 0.1154);
MVP		0.99
MPC		0.076
ClinPred		0.81	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.78
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs768471577; hg19: chr7-107334921;