Submissions for variant NM_000112.4(SLC26A2):c.532C>T (p.Arg178Ter)

gnomAD frequency: 0.00012  dbSNP: rs104893919

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000412934	SCV000227019	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000412934	SCV000491205	pathogenic	not provided	2024-05-10	criteria provided, single submitter	clinical testing	Common pathogenic variant associated with SLC26A2-related chondrodysplasias, typically associated with a severe phenotype when in trans with a second loss-of-function variant (PMID: 21155763, 11241838); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26990548, 11241838, 8528239, 18925670, 15294877, 11448940, 31589614, 31345219, 35587316, 36007841, 32333414, 21155763, 15316973)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590163	SCV000695419	pathogenic	Sulfate transporter-related osteochondrodysplasia	2017-02-02	criteria provided, single submitter	clinical testing	Variant summary: The SLC26A2 c.532C>T (p.Arg178X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC26A2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1724delA). One in silico tool predicts a damaging outcome for this variant, which has been confirmed by at least one functional study (Karniski_2004). This variant was found in 13/120994 control chromosomes at a frequency of 0.0001074, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC26A2 variant (0.002958). This variant has been reported in multiple STRO patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690242	SCV000817923	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg178*) in the SLC26A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A2 are known to be pathogenic (PMID: 7923357, 10482955, 11241838). This variant is present in population databases (rs104893919, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with SLC26A2-related disease (PMID: 8528239, 15316973, 18925670, 21155763). ClinVar contains an entry for this variant (Variation ID: 4092). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000779467	SCV000916095	pathogenic	SLC26A2-related disorder	2018-10-19	criteria provided, single submitter	clinical testing	The SLC26A2 c.532C>T (p.Arg178Ter) variant is a stop-gained variant. Across a selection of literature, the p.Arg178Ter variant has been reported in a compound heterozygous state in at least 13 probands (Superti-Furga 1996; Macías-Gómez et al. 2004; Panzer et al. 2008; Barbosa et al. 2011; Mattos et al. 2014). In at least one family an unaffected father was heterozygous for this variant. The p.Arg178Ter variant was absent from at least 200 controls, but is reported at a frequency of 0.00029 in the Latino population from the Genome Aggregation Database. In Xenopus oocytes, the p.Arg178Ter variant was shown to have significantly reduced (<10%) sulfate transport compared to wildtype, and similar findings were noted in HEK-293 cells (Karniski et al. 2001; Karniski et al. 2004). Based on the collective evidence, the p.Arg178Ter variant is classified as pathogenic for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Genetics, Inc.	RCV000175526	SCV001193834	pathogenic	Multiple epiphyseal dysplasia type 4	2019-12-11	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.532C>T(R178*) is classified as pathogenic in the context of SLC26A2-related disorders and is associated with Achondrogenesis Type 1B. Sources cited for classification include the following: PMID 11448940, 21155763 and 8528239. Classification of NM_000112.3(SLC26A2):c.532C>T(R178*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Myriad Genetics, Inc.	RCV000004310	SCV001194195	pathogenic	Diastrophic dysplasia	2019-12-11	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.532C>T(R178*) is classified as pathogenic in the context of SLC26A2-related disorders and is associated with Achondrogenesis Type 1B. Sources cited for classification include the following: PMID 11448940, 21155763 and 8528239. Classification of NM_000112.3(SLC26A2):c.532C>T(R178*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Myriad Genetics, Inc.	RCV000023568	SCV001194196	pathogenic	Achondrogenesis, type IB	2019-12-11	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.532C>T(R178*) is classified as pathogenic in the context of SLC26A2-related disorders and is associated with Achondrogenesis Type 1B. Sources cited for classification include the following: PMID 11448940, 21155763 and 8528239. Classification of NM_000112.3(SLC26A2):c.532C>T(R178*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Myriad Genetics, Inc.	RCV001030754	SCV001194197	pathogenic	3MC syndrome 2	2019-12-11	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.532C>T(R178*) is classified as pathogenic in the context of SLC26A2-related disorders and is associated with Achondrogenesis Type 1B. Sources cited for classification include the following: PMID 11448940, 21155763 and 8528239. Classification of NM_000112.3(SLC26A2):c.532C>T(R178*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000412934	SCV002020668	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing
DASA	RCV000411745	SCV002061200	pathogenic	Atelosteogenesis type II	2022-01-05	criteria provided, single submitter	clinical testing	The c.532C>T;p.(Arg178*) variant creates a premature translational stop signal in the SLC26A2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 4092; PMID: 20301524; 21155763; 18925670; 15316973; 11241838) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11448940; 15294877) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104893919 – gnomAD 0.01118%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg178*) was detected in trans with a pathogenic variant (PMID: 21155763; 18925670; 15316973) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV000023568	SCV002099437	pathogenic	Achondrogenesis, type IB		criteria provided, single submitter	research
Baylor Genetics	RCV000023568	SCV004201741	pathogenic	Achondrogenesis, type IB	2024-03-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000690242	SCV005670682	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2024-06-05	criteria provided, single submitter	clinical testing
OMIM	RCV000004310	SCV000024478	pathogenic	Diastrophic dysplasia	2008-11-15	no assertion criteria provided	literature only
OMIM	RCV000023568	SCV000044859	pathogenic	Achondrogenesis, type IB	2008-11-15	no assertion criteria provided	literature only
GeneReviews	RCV000004310	SCV000086703	not provided	Diastrophic dysplasia		no assertion provided	literature only
Counsyl	RCV000411745	SCV000487411	pathogenic	Atelosteogenesis type II	2016-02-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000023568	SCV001452790	pathogenic	Achondrogenesis, type IB	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000412934	SCV001799156	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412934	SCV001958259	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000412934	SCV001963834	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000411745	SCV002015216	pathogenic	Atelosteogenesis type II	2021-11-17	no assertion criteria provided	clinical testing	This heterozygous stop gain variant has been previously reported by Macías-Gómez NM et al in 2004 in a Mexican patient. In our study this variant is present in compound heterozygous state with another mis-sense variant-c.1382C>T (p.A461V). The allele frequency-0.0131% in gnomAD (Aggregated) database and not reported in 1000g till date. Phenotype observed in the proband was severe shortening of all long bones, exaggerated lumbar lordosis, big toe and radial shortening. Atelosteogenesis II is an autosomal recessive disorder and can be caused by homozygous or compound heterozygous mutations. Based on phenotypic observation and available literature, we classify this variant as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000779467	SCV005361527	pathogenic	SLC26A2-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The SLC26A2 c.532C>T variant is predicted to result in premature protein termination (p.Arg178*). This variant is one of the most common pathogenic changes in the SLC26A2 gene, and has been documented in multiple affected individuals (Barbosa et al. 2011. PubMed ID: 21155763; https://www.ncbi.nlm.nih.gov/books/NBK1350/). When detected in the compound heterozygous or homozygous states, it is reported in patients with severe SLC26A2 associated phenotypes of achondrogenesis type IB, diastrophic dysplasia, and atelosteogenesis type 2 (Superti-Furga et al.1996. PubMed ID: 8528239; Panzer et al. 2008. PubMed ID: 18925670). Functional studies support the pathogenicity of this change (Karniski. 2001. PubMed ID: 11448940). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.