NM_000112.4(SLC26A2):c.1273A>G (p.Asn425Asp) AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001851641.15

Allele description [Variation Report for NM_000112.4(SLC26A2):c.1273A>G (p.Asn425Asp)]

NM_000112.4(SLC26A2):c.1273A>G (p.Asn425Asp)

Gene:

SLC26A2:solute carrier family 26 member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q32

Genomic location:

Preferred name:

NM_000112.4(SLC26A2):c.1273A>G (p.Asn425Asp)

HGVS:

NC_000005.10:g.149980866A>G
NG_007147.2:g.21984A>G
NM_000112.4:c.1273A>GMANE SELECT
NP_000103.2:p.Asn425Asp
NP_000103.2:p.Asn425Asp
LRG_684t1:c.1273A>G
LRG_684:g.21984A>G
LRG_684p1:p.Asn425Asp
NC_000005.9:g.149360429A>G
NM_000112.3:c.1273A>G
P50443:p.Asn425Asp

Protein change:

N425D; ASN425ASP

Links:

UniProtKB: P50443#VAR_007437; OMIM: 606718.0006; dbSNP: rs104893920

NCBI 1000 Genomes Browser:

rs104893920

Molecular consequence:

NM_000112.4:c.1273A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Achondrogenesis, type IB (ACG1B)
Synonyms:: Achondrogenesis Fraccaro type
Identifiers:: MONDO: MONDO:0010966; MedGen: C0265274; Orphanet: 932; Orphanet: 93298; OMIM: 600972

Name:: Atelosteogenesis type II (AO2)
Synonyms:: NEONATAL OSSEOUS DYSPLASIA I; Neonatal osseous dysplasia 1; Atelosteogenesis type 2
Identifiers:: MONDO: MONDO:0009727; MedGen: C1850554; Orphanet: 56304; OMIM: 256050

Name:: Multiple epiphyseal dysplasia type 4 (EDM4)
Synonyms:: MULTIPLE EPIPHYSEAL DYSPLASIA WITH BILAYERED PATELLAE; MULTIPLE EPIPHYSEAL DYSPLASIA WITH CLUBFOOT; MULTIPLE EPIPHYSEAL DYSPLASIA, AUTOSOMAL RECESSIVE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009189; MedGen: C1847593; Orphanet: 93307; OMIM: 226900

Name:: Diastrophic dysplasia (DTD)
Synonyms:: Diastrophic dwarfism
Identifiers:: MONDO: MONDO:0009107; MedGen: C0220726; Orphanet: 628; OMIM: 222600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002240090	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11448940, 8528239, 9342225, 21155763, 28492532
SCV002780742	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 23, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005416101	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002240090

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 8, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002780742

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 23, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005416101

Juno Genomics, Hangzhou Juno Genomics, Inc

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype.

Karniski LP.

Hum Mol Genet. 2001 Jul 1;10(14):1485-90.

PubMed [citation]

PMID:: 11448940

Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene.

Superti-Furga A, Hästbacka J, Wilcox WR, Cohn DH, van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R.

Nat Genet. 1996 Jan;12(1):100-2. No abstract available.

PubMed [citation]

PMID:: 8528239

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002240090.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 11448940). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A2 protein function. ClinVar contains an entry for this variant (Variation ID: 4093). This missense change has been observed in individual(s) with diastrophic dysplasia (PMID: 8528239, 9342225, 21155763). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 425 of the SLC26A2 protein (p.Asn425Asp).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002780742.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005416101.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PM2_Supporting+PM3_VeryStrong+PS3_Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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