5-149980602-CTTGTTG-CTTG

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM4_SupportingPP5_Very_Strong

The NM_000112.4(SLC26A2):c.1020_1022delTGT(p.Val341del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V340V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 7.97

Publications

8 publications found

Variant links:

Genes affected

SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]

SLC26A2 Gene-Disease associations (from GenCC):

achondrogenesis type IB
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
atelosteogenesis type II
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics
diastrophic dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
multiple epiphyseal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
multiple epiphyseal dysplasia type 4
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P

SLC26A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000112.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 5-149980602-CTTG-C is Pathogenic according to our data. Variant chr5-149980602-CTTG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65558.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
SLC26A2	NM_000112.4 link	c.1020_1022delTGT	p.Val341del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000286298.5	NP_000103.2	P50443
SLC26A2	XM_017009191.3 link	c.1020_1022delTGT	p.Val341del	disruptive_inframe_deletion	Exon 3 of 4		XP_016864680.1	P50443

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5 link	c.1020_1022delTGT	p.Val341del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_000112.4	ENSP00000286298.4		P50443
SLC26A2	ENST00000503336.1 link	c.372+2262_372+2264delTGT		intron_variant	Intron 1 of 1	3		ENSP00000426053.1		H0YA38

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

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

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251132

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461764

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000428

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1111938

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II

Pathogenic:3

Jan 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1020_1022del, results in the deletion of 1 amino acid(s) of the SLC26A2 protein (p.Val341del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777472333, gnomAD 0.03%). This variant has been observed in individuals with SLC26A2-related disorders (PMID: 8528239, 9637425, 10482955, 31218223). ClinVar contains an entry for this variant (Variation ID: 65558). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC26A2 function (PMID: 11448940). For these reasons, this variant has been classified as Pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM4+PM3_VeryStrong+PS3_Supporting -

not provided

Pathogenic:3

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate abnormal sulfate transporter activity (Superti-Furga et al. 1996; Karniski et al. 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region; Reported previously as c.1045_1047delGTT or p.Val340del using alternate nomenclature; This variant is associated with the following publications: (PMID: 15294877, 8528239, 20301689, 10482955, 31218223, 11448940, 9637425) -

Oct 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC26A2 c.1020_1022delTGT; p.Val341del variant (rs121908077) has been described in association with SLC26A2-related chondrodysplasias (Cai 1998, Superti-Furga 1996). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 65558) and is observed in the general population at an overall frequency of 0.01% (31/276822 alleles) in the Genome Aggregation Database. This variant deletes a single valine residue, leaving the rest of the protein product in-frame. Functional characterization of the variant protein demonstrates reduced protein expression and abnormal sulfate transporter activity (Karniski 2001, Karniski 2004, Superti-Furga 1996). Based on available information, this variant is considered pathogenic. References: Cai G et al. Mutational analysis of the DTDST gene in a fetus with achondrogenesis type 1B. Am J Med Genet. 1998 Jun 16;78(1):58-60. Karniski L et al. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. Hum Mol Genet. 2001 Jul 1;10(14):1485-90. Karniski L et al. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet. 2004 Oct 1;13(19):2165-71. Superti-Furga et al. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet. 1996 Jan;12(1):100-2. -

Achondrogenesis, type IB

Pathogenic:2

Jun 16, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 23, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diastrophic dysplasia

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Medical Molecular Genetics Department, National Research Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The c.1020_1022delTGT; p.Val341del variant is an in-frame deletion, with low frequency in gnomAD (0.0064%). Previously reported in patients with chondrodysplasia (PMID: 8702127, PMID: 37265969, PMID: 38956600). It is classified as pathogenic (PP5, PP3, PM2) according to ACMG guidelines. -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1850554:Atelosteogenesis type II

Pathogenic:1

Nov 03, 2021

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000112.3(SLC26A2):c.1020_1022delTGT(V341del) is an in-frame deletion classified as likely pathogenic in the context of SLC26A2-related disorders. V341del has been observed in cases with relevant disease (PMID: 9637425, 8528239, 10482955). Functional assessments of this variant are available in the literature (PMID: 11448940, 15294877). V341del has been observed in population frequency databases (gnomAD: EAS 0.03%). In summary, NM_000112.3(SLC26A2):c.1020_1022delTGT(V341del) is an in-frame deletion variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Atelosteogenesis type II

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sulfate transporter-related osteochondrodysplasia

Pathogenic:1

Jul 28, 2016

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SLC26A2 c.1020_1022delTGT (p.Val341del) variant involves the deletion of a Valine in the predicted seventh transmembrane domain of the SLC26A2 protein. One in silico tool predicts a damaging outcome for this variant. This variant was found in 17/121404 control chromosomes at a frequency of 0.00014, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC26A2 variant (0.002958). The variant has been reported in multiple affected individuals in the homozygous and compound heterozygous state, and has been shown to result in impaired ability for sulfate uptake in HEK cells (comparable to negative control cells). In these transfected cells, the protein is not detected by either immunoblot analysis or confocal immunofluorescent microscopy, suggesting that this mutation is either poorly expressed or the protein is rapidly degraded in mammalian cells (Karniski_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, and this variant is considered a common disease variant. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=74/26

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over