5-149980602-CTTG-C

Variant names:

• chr5-149980602-CTTG-C
• rs121908077
• NM_000112.4:c.1020_1022delTGT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SLC26A2 NM_000112.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 65558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149980602-CTTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A2	NM_000112.4	c.1020_1022delTGT	p.Val341del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000286298.5	NP_000103.2
SLC26A2	XM_017009191.3	c.1020_1022delTGT	p.Val341del	disruptive_inframe_deletion	Exon 3 of 4		XP_016864680.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152144 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251132 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135730

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 SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461764 Hom.: 0 AF XY: 0.0000811 AC XY: 59 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74440

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:3

-

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 -

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. -

not provided Pathogenic:3

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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) -

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;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. -

Diastrophic dysplasia Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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: rs121908077; hg19: chr5-149360165;