2-44320329-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000341.4(SLC3A1):c.1750del(p.Arg584GlufsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SLC3A1 NM_000341.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.799

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]

PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PP5: Variant 2-44320329-CA-C is Pathogenic according to our data. Variant chr2-44320329-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC3A1	NM_000341.4	c.1750del	p.Arg584GlufsTer14	frameshift_variant	10/10	ENST00000260649.11
PREPL	NM_001171613.2	c.*1026del		3_prime_UTR_variant	14/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC3A1	ENST00000260649.11	c.1750del	p.Arg584GlufsTer14	frameshift_variant	10/10	1	NM_000341.4	P1
PREPL	ENST00000409411.6	c.*1026del		3_prime_UTR_variant	14/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251198 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystinuria Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2018	The p.Arg584GlufsX14 (NM_000341.3 c.1750delA) variant in SLC3A1 (legacy nomencla ture c.1749delA) has been reported in at least 8 individuals with cystinuria, in cluding 1 confirmed compound heterozygote (Gasparini 1995, Font-Llitjos 2005, Ch illaron 2010, Gaildrat 2017). This variant has also been reported in ClinVar (Va riation ID#375410). While this variant occurs in the last exon and is expected n ot to undergo nonsense-mediated decay, in vitro functional studies have shown th e region downstream of this variant in SLC3A1 is essential for forming disulfide bonds and its absence may disrupt biogenesis (Rius 2012). Additionally, multipl e frameshift variants have been reported downstream of this position in patients with cystinuria, suggesting deletion of this region may have functional consequ ence. This variant has been identified in 7/111436 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs10 57519470), though this frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to full y establish its clinical significance, the p.Arg584GlufsX14 variant is likely pa thogenic for cystinuria in an autosomal recessive manner based upon observations in affected individuals, functional studies, and predicted impact to the protei n. ACMG/AMP Criteria applied: PM2, PM3, PVS1_Moderate, PS3_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 18, 2016	The c.1750delA (p.Arg584Glufs*14) frameshift variant (also referred to as c.1749delA in the medical literature) in the SLC3A1 gene has been previously reported in several individuals who were diagnosed with cystinuria (Gasparini et al., 1995; Chillaron J et al., 2010). Additional frameshift variants that are further downstream (towards the 3’-end of the gene) have also been reported in affected individuals (Chillaron J et al., 2010). Although this variant is present in the last exon of the gene, the C-terminal tail of this protein that is predicted to be lost as a result of this variant contains cysteine residues that are critical for disulfide bond formation and biogenesis of the transporter (Rius M et al., 2016) .This variant is either absent in the population databases (Exome Sequencing Project, 1000 Genomes) or present at a frequency below that of the disease allele (<0.01%). Therefore, this collective evidence supports the classification of the c.1750delA (p.Arg584Glufs*14) as a Likely pathogenic variant for Cystinuria. We have confirmed this finding in our laboratory using Sanger sequencing. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 12, 2023	This sequence change creates a premature translational stop signal (p.Arg584Glufs*14) in the SLC3A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 102 amino acid(s) of the SLC3A1 protein. This variant is present in population databases (rs775827496, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with cystinuria (PMID: 7573036). This variant is also known as 1749delA. ClinVar contains an entry for this variant (Variation ID: 375410). This variant disrupts a region of the SLC3A1 protein in which other variant(s) (p.Glu585Alafs*24) have been determined to be pathogenic (PMID: 11748844, 25964309, 28717662; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs775827496; hg19: chr2-44547468;