rs200483989

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000341.4(SLC3A1):​c.808C>T​(p.Arg270*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,613,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

SLC3A1
NM_000341.4 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.15
Variant links:
Genes affected
SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-44286074-C-T is Pathogenic according to our data. Variant chr2-44286074-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 336195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44286074-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC3A1NM_000341.4 linkc.808C>T p.Arg270* stop_gained Exon 4 of 10 ENST00000260649.11 NP_000332.2 Q07837-1A0A0S2Z4E1
SLC3A1XM_011533047.4 linkc.808C>T p.Arg270* stop_gained Exon 4 of 10 XP_011531349.1 B8ZZK1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC3A1ENST00000260649.11 linkc.808C>T p.Arg270* stop_gained Exon 4 of 10 1 NM_000341.4 ENSP00000260649.6 Q07837-1
ENSG00000285542ENST00000649044.1 linkn.*819C>T non_coding_transcript_exon_variant Exon 9 of 15 ENSP00000497083.1 A0A3B3IS24
ENSG00000285542ENST00000649044.1 linkn.*819C>T 3_prime_UTR_variant Exon 9 of 15 ENSP00000497083.1 A0A3B3IS24

Frequencies

GnomAD3 genomes
AF:
0.000178
AC:
27
AN:
152062
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00634
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000394
AC:
99
AN:
251434
Hom.:
0
AF XY:
0.000375
AC XY:
51
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00883
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000187
AC:
273
AN:
1461602
Hom.:
1
Cov.:
31
AF XY:
0.000182
AC XY:
132
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00696
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000531
Gnomad4 OTH exome
AF:
0.000480
GnomAD4 genome
AF:
0.000178
AC:
27
AN:
152062
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00634
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000811
Hom.:
0
Bravo
AF:
0.000185
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000222
AC:
27
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystinuria Pathogenic:6
Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SLC3A1 c.808C>T (p.Arg270Ter) variant has been reported in at least 11 individuals with cystinuria, including two siblings, in a homozygous state, and one individual in a compound heterozygous state (Pras et al. 1995; Endsley et al. 1997; Gitomet et al. 1998; Botzenhart et al. 2002; Chatzikyriakidou et al. 2005; Merieau et al. 2009). Four of the individuals homozygous for the p.Arg270Ter variant were of Ashkenazi Jewish ancestry (Pras et al. 1995). Control data are not available for the variant which is reported at a frequency of 0.00041 in the European (non-Finnish) population of the Exome Aggregation Consortium database. Based on the evidence and due to the potential impact of stop-gained variants, the p.Arg270Ter variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 10, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cystinuria (MIM#220100). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with recessive disease, there are reports of affected carriers (PMID: 15635077, 25964309). (I) 0112 - The dominant condition associated with this gene has incomplete penetrance (PMID: 22480232). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (101 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in homozygous and compound heterozygous individuals with cystinuria (ClinVar). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_000341.3(SLC3A1):c.2014_2015delinsTA; p.(Ala672*)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg270*) in the SLC3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC3A1 are known to be pathogenic (PMID: 24610330, 25109415, 25964309). This variant is present in population databases (rs200483989, gnomAD 0.8%). This premature translational stop signal has been observed in individuals with cystinuria (PMID: 7539209, 28646536). ClinVar contains an entry for this variant (Variation ID: 336195). For these reasons, this variant has been classified as Pathogenic. -

Jan 25, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

NM_000341.3:c.808C>T in the SLC3A1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Botzenhart E et al. identified this variant in two patients with cystinuria, including one in homozygous state amd one in compound heterozygous state (R270X/M467T) (PMID: 12234283 ). Gitomer WL et al. found this mutation in 3 patients in homozygous status, two were siblings (PMID: 9768685). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP4. -

Jun 12, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 21, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP4, PM3, PVS1 -

Nov 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SLC3A1: PVS1, PM2 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

SLC3A1-related disorder Pathogenic:1
Aug 29, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The SLC3A1 c.808C>T variant is predicted to result in premature protein termination (p.Arg270*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive cystinuria (Pras et al. 1995. PubMed ID: 7539209; Endsley et al. 1997. PubMed ID: 9186880; Botzenhart et al. 2002. PubMed ID: 12234283; Chatzikyriakidou et al. 2005. PubMed ID: 16225397; Tostivint et al. 2017. PubMed ID: 28646536) and has been reported to co-segregate with disease in at least one family (Gitomer et al. 1998. PubMed ID: 9768685). This variant is reported in 0.88% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been described as a possible founder variant (Pras et al. 1995. PubMed ID: 7539209). Nonsense variants in SLC3A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Autism spectrum disorder Pathogenic:1
Jul 28, 2023
Gene Friend Way, National Innovation Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg270*) in the SLC3A1 gene. It is expected to result in an absent or disrupted protein product which can manifest as kidney disease. In autism, there have been studies that show a link between ASD and kidney disease. PMID: 33340339. Mutations in SLC3A1 are known as the causative factor of cystinuria, which involving the defective transepithelial transport of cystine and the ability to reabsorb cystine into the blood (PMID: 25109415, 25964309). Meanwhile, plasma concentration of cystein is significantly decreased in ASD children (PMID: 15585776). In our study, an ASD patient carries this SLC3A1 rs200483989 mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.78
D
Vest4
0.85
GERP RS
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200483989; hg19: chr2-44513213; COSMIC: COSV53223713; API