rs200483989

Variant names:

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

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]

SLC3A1 links:

ENSG00000285542 (HGNC:):

ENSG00000285542 links:

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
SLC3A1	NM_000341.4 link	c.808C>T	p.Arg270*	stop_gained	Exon 4 of 10	ENST00000260649.11	NP_000332.2	Q07837-1A0A0S2Z4E1
SLC3A1	XM_011533047.4 link	c.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	UniProt
SLC3A1	ENST00000260649.11 link	c.808C>T	p.Arg270*	stop_gained	Exon 4 of 10	1	NM_000341.4	ENSP00000260649.6	Q07837-1
ENSG00000285542	ENST00000649044.1 link	n.*819C>T		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000497083.1	A0A3B3IS24
ENSG00000285542	ENST00000649044.1 link	n.*819C>T		3_prime_UTR_variant	Exon 9 of 15			ENSP00000497083.1	A0A3B3IS24

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

152062

Hom.:

Cov.:

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:

AN:

251434

Hom.:

AF XY:

0.000375

AC XY:

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.:

Cov.:

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:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

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.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 12, 2024	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	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 -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SLC3A1: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 21, 2024	PP4, PM3, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

SLC3A1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

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

Pathogenic, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

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

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.78

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over