rs80338848

Variant names:

• chr7-107675051-T-C
• rs80338848
• NM_000441.2:c.707T>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.707T>C​(p.Leu236Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,613,988 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 (★★). ClinVar reports functional evidence for this variant: "SCV006072304: The most pronounced variant effect results in loss of pendrin-induced chloride and iodide transport (e.g. Scott_2000). PMID:10861298" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L236V) has been classified as Pathogenic. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 O:1
• Conservation: PhyloP100: 7.54
• Publications: 71 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006072304: The most pronounced variant effect results in loss of pendrin-induced chloride and iodide transport (e.g. Scott_2000). PMID: 10861298; SCV000616878: Published functional studies demonstrate a damaging effect due to improper intracellular localization of pendrin and loss of pendrin-induced iodide and chloride transport (Scott et al., 2000; Yoon et al., 2008); SCV000958105: Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 10861298, 12354788, 18310264).; SCV001551437: Functional studies have shown that this variant causes protein mislocalization and impaired iodide/chloride transport activity compared to wild type (Scott_2000_PMID:10861298, Rotman-Pikielny_2002_PMID:12354788, Yoon_2008_PMID:18310264).; SCV000060160: "One in vitro functional analysis study suggests the variant may impact normal intracellular trafficking of the protein (Rotman-Pikielny 2002)."; SCV000916169: Functional studies by Rotman-Pikielny et al. (2002) demonstrated that the variant protein is retained in the endoplasmic reticulum (ER) whereas the wild type protein targets to the plasma membrane. Yoon et al. (2008) confirmed the initial localization of the p.Leu236Pro variant protein in the ER and showed that after time, the protein was concentrated at the centrosome. They further determined that Cl-/HCO3- ion exchange activity of the variant protein was notably decreased, and that the variant was not temperature sensitive. PMID:12192042 PMID:18775892
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000441.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107675050-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 43565.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 7-107675051-T-C is Pathogenic according to our data. Variant chr7-107675051-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.707T>C	p.Leu236Pro	missense	Exon 6 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.707T>C	p.Leu236Pro	missense	Exon 6 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.707T>C	p.Leu236Pro	missense	Exon 5 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.707T>C	p.Leu236Pro	missense	Exon 6 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152190 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

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: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000274 AC: 69 AN: 251476 AF XY: 0.000250

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000487 AC: 712 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.000483 AC XY: 351 AN XY: 727204

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000622 AC: 692 AN: 1111938

Other (OTH) AF: 0.000298 AC: 18 AN: 60384

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152190 Hom.: 0 Cov.: 30 AF XY: 0.000242 AC XY: 18 AN XY: 74354

African (AFR) AF: 0.000145 AC: 6 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000552 Hom.: 1

Bravo AF: 0.000276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	not provided (10)
7	-	-	Pendred syndrome (8)
2	-	-	Autosomal recessive nonsyndromic hearing loss 4 (2)
2	-	-	SLC26A4-related disorder (2)
1	-	-	Hearing impairment (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.99
MPC		0.061
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.98
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80338848; hg19: chr7-107315496;