VCV000242374.34 - ClinVar

NM_022042.4(SLC26A1):c.554C>T (p.Thr185Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022042.4(SLC26A1):c.554C>T (p.Thr185Met)

Variation ID: 242374 Accession: VCV000242374.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 991150 (GRCh38) [ NCBI UCSC ] 4: 984938 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 24, 2016	Dec 22, 2024	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000203.5:c.299+3201G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_022042.4:c.554C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071325.2:p.Thr185Met	missense
NM_134425.4:c.554C>T	NP_602297.1:p.Thr185Met	missense
NM_213613.4:c.554C>T	NP_998778.1:p.Thr185Met	missense
NC_000004.12:g.991150G>A
NC_000004.11:g.984938G>A
NG_008103.1:g.9154G>A
NG_033042.1:g.7287C>T
LRG_1277:g.9154G>A
LRG_1277t1:c.299+3201G>A
	Q9H2B4:p.Thr185Met

... more HGVS ... less HGVS

Protein change

T185M

Other names

Canonical SPDI

NC_000004.12:991149:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00020

Exome Aggregation Consortium (ExAC) 0.00025

The Genome Aggregation Database (gnomAD), exomes 0.00025

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039

1000 Genomes Project 30x 0.00047

1000 Genomes Project 0.00060

Links

ClinGen: CA2801632 UniProtKB: Q9H2B4#VAR_077135 OMIM: 610130.0001 dbSNP: rs139024319 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IDUA		-	-	GRCh38 GRCh37	1408	2190
SLC26A1		-	-	GRCh38 GRCh37	3	784

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Nephrolithiasis, calcium oxalate	Likely pathogenic (2)	criteria provided, single submitter	Jan 1, 2016	RCV000234843.8
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Dec 21, 2023	RCV000681878.29
SLC26A1-related disorder	Uncertain significance (1)	no assertion criteria provided	May 3, 2024	RCV004755826.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrolithiasis susceptibility caused by SLC26A1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368733.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Uncertain significance (Dec 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003264181.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 27210743‚ 30586318‚ 36719378 Comment: This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 185 of the SLC26A1 protein (p.Thr185Met). … (more) This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 185 of the SLC26A1 protein (p.Thr185Met). This variant is present in population databases (rs139024319, gnomAD 0.04%). This missense change has been observed in individual(s) with nephrolithiasis (PMID: 27210743, 30586318). ClinVar contains an entry for this variant (Variation ID: 242374). 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 SLC26A1 protein function. Experimental studies have shown that this missense change affects SLC26A1 function (PMID: 27210743, 36719378). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely pathogenic (Apr 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001371195.25 First in ClinVar: Jul 16, 2020 Last updated: Dec 22, 2024	Number of individuals with the variant: 1
Likely pathogenic (Sep 16, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: research	not provided Affected status: yes Allele origin: germline	Gharavi Laboratory, Columbia University Accession: SCV000809357.1 First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018
Pathogenic (May 15, 2023)	no assertion criteria provided Method: literature only	NEPHROLITHIASIS, CALCIUM OXALATE, 1 (1 patient) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000292030.3 First in ClinVar: Jul 03, 2016 Last updated: May 20, 2023	Publications: PubMed (2) PubMed: 27210743‚ 36719378 Comment on evidence: In a boy of Macedonian descent with calcium oxalate nephrolithiasis (CAON1; 167030), Gee et al. (2016) identified compound heterozygous mutations in the SLC26A1 gene: a … (more) In a boy of Macedonian descent with calcium oxalate nephrolithiasis (CAON1; 167030), Gee et al. (2016) identified compound heterozygous mutations in the SLC26A1 gene: a c.554C-T transition (c.554C-T, NM_022042.3) in exon 2, resulting in a thr185-to-met (T195M) substitution, and a c.1073C-T transition in exon 3, resulting in a ser358-to-leu (S358L; 610130.0002) substitution. The mutations occurred at conserved residues and both had been reported individually at a low frequency in the Exome Variant Server and dbSNP databases (less than 0.0006), and in the ExAC database (26 in 104,290 alleles for T185M and 10 in 24,944 alleles for S358L). Transfection of the mouse ortholog of the T185M mutation into HEK293 cells resulted in lack of proper expression at the plasma membrane due to retention of the mutant protein in the endoplasmic reticulum (ER). The T185M mutant ortholog was not properly glycosylated and was degraded via the ER-associated protein degradation pathway. The S358L mouse ortholog reached the plasma membrane, but a significant portion of mutant protein was trapped in the ER, suggesting a processing defect. The overall protein levels of the mutant proteins were lower than wildtype, suggesting poor protein stability, and both mutations also caused a decrease in transporter activity compared to wildtype. The patient had onset of acute renal failure due to calcium oxalate nephrolithiasis at 5 years of age. He also had ureteropelvic junction obstruction necessitating surgery. Urinary analysis showed hyperoxaluria. Pfau et al. (2023) found that the T185M variant reduced sulfate transport when expressed in Xenopus oocytes, consistent with a loss of function; this mutation acted in a dominant-negative manner. (less)
Uncertain significance (May 03, 2024)	no assertion criteria provided Method: clinical testing	SLC26A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362240.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SLC26A1 c.554C>T variant is predicted to result in the amino acid substitution p.Thr185Met. This variant has been reported in the compound heterozygous state with … (more) The SLC26A1 c.554C>T variant is predicted to result in the amino acid substitution p.Thr185Met. This variant has been reported in the compound heterozygous state with the p.Ser358Leu variant in an individual with nephrolithiasis (Gee et al. 2016. PubMed ID: 27210743). In a separate study, this variant was reported in a patient with nephropathy; however, this patient also had the p.Ser358Leu variant (phase was not determined) and a variant in INF2 (Patient CDK250 in Table S7, Groopman. 2019 et al. PubMed ID: 30586318). In addition, the p.Thr185Met and p.Ser358Leu variants were documented separately in individuals from the German Chronic Kidney Disease (GCKD) cohort (Pfau et al. 2023. PubMed ID: 36719378). Functional studies have shown that the p.Thr185Met variant causes a defect in protein folding/trafficking and an ~25% reduction of transport activity, supportive of dominant negative effect (Groopman et al. 2018. PubMed ID: 30586318; Pfau et al. 2023. PubMed ID 36719378). This variant is reported in 0.046% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations in ClinVar ranging from pathogenic to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/242374/). It has been noted that further evidence is needed to clarify the association of biallelic variants in SLC26A1 with disease per ClinGen criteria (Pfau et al. 2023. PubMed ID: 36719378). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 185 of the SLC26A1 protein (p.Thr185Met). This variant is present in population databases (rs139024319, gnomAD 0.04%). This missense change has been observed in individual(s) with nephrolithiasis (PMID: 27210743, 30586318). ClinVar contains an entry for this variant (Variation ID: 242374). 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 SLC26A1 protein function. Experimental studies have shown that this missense change affects SLC26A1 function (PMID: 27210743, 36719378). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The SLC26A1 c.554C>T variant is predicted to result in the amino acid substitution p.Thr185Met. This variant has been reported in the compound heterozygous state with the p.Ser358Leu variant in an individual with nephrolithiasis (Gee et al. 2016. PubMed ID: 27210743). In a separate study, this variant was reported in a patient with nephropathy; however, this patient also had the p.Ser358Leu variant (phase was not determined) and a variant in INF2 (Patient CDK250 in Table S7, Groopman. 2019 et al. PubMed ID: 30586318). In addition, the p.Thr185Met and p.Ser358Leu variants were documented separately in individuals from the German Chronic Kidney Disease (GCKD) cohort (Pfau et al. 2023. PubMed ID: 36719378). Functional studies have shown that the p.Thr185Met variant causes a defect in protein folding/trafficking and an ~25% reduction of transport activity, supportive of dominant negative effect (Groopman et al. 2018. PubMed ID: 30586318; Pfau et al. 2023. PubMed ID 36719378). This variant is reported in 0.046% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations in ClinVar ranging from pathogenic to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/242374/). It has been noted that further evidence is needed to clarify the association of biallelic variants in SLC26A1 with disease per ClinGen criteria (Pfau et al. 2023. PubMed ID: 36719378). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
SLC26A1 is a major determinant of sulfate homeostasis in humans.	Pfau A	The Journal of clinical investigation	2023	PMID: 36719378
Diagnostic Utility of Exome Sequencing for Kidney Disease.	Groopman EE	The New England journal of medicine	2019	PMID: 30586318
Mutations in SLC26A1 Cause Nephrolithiasis.	Gee HY	American journal of human genetics	2016	PMID: 27210743

Text-mined citations for rs139024319 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_022042.4(SLC26A1):c.554C>T (p.Thr185Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139024319 ...