2-44320329-CAA-C

Position:

• chr2-44320329-CAA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000260649.11(SLC3A1):​c.1749_1750del​(p.Glu585AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC3A1 ENST00000260649.11 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.15

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 Likely_pathogenic. Variant got 8 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 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-44320329-CAA-C is Pathogenic according to our data. Variant chr2-44320329-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 953279.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.1749_1750del	p.Glu585AlafsTer24	frameshift_variant	10/10	ENST00000260649.11	NP_000332.2
PREPL	NM_001171613.2	c.*1025_*1026del		3_prime_UTR_variant	14/14	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11	c.1749_1750del	p.Glu585AlafsTer24	frameshift_variant	10/10	1	NM_000341.4	ENSP00000260649	P1
PREPL	ENST00000409411.6	c.*1025_*1026del		3_prime_UTR_variant	14/14	1	NM_001171613.2	ENSP00000387095	P4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2019

This sequence change results in a premature translational stop signal in the SLC3A1 gene (p.Glu585Alafs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acids of the SLC3A1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cystinuria (PMID: 28717662, Invitae). This variant disrupts the C-terminus of the SLC3A1 protein. Other variant(s) that disrupt this region (p.Arg567Glyfs*9, p.Gly600Glu, p.Gln659*) have been observed in individuals with SLC3A1-related conditions (PMID: 25964309, 28717662, 25964309, 11748844). This suggests that this may be a clinically significant region of the protein. 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)		0.0		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

Other links and lift over

dbSNP: rs1672820246; hg19: chr2-44547468;