rs386833809
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_003982.4(SLC7A7):βc.1460delβ(p.Cys487LeufsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. C487C) has been classified as Likely benign.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 32)
Exomes π: 0.000012 ( 0 hom. )
Consequence
SLC7A7
NM_003982.4 frameshift
NM_003982.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.25
Genes affected
SLC7A7 (HGNC:11065): (solute carrier family 7 member 7) The protein encoded by this gene is the light subunit of a cationic amino acid transporter. This sodium-independent transporter is formed when the light subunit encoded by this gene dimerizes with the heavy subunit transporter protein SLC3A2. This transporter is found in epithelial cell membranes where it transfers cationic and large neutral amino acids from the cell to the extracellular space. Defects in this gene are a cause of lysinuric protein intolerance (LPI). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2011]
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ACMG classification
Classification made for transcript
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. Fraction of 0.0495 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-22773685-AC-A is Pathogenic according to our data. Variant chr14-22773685-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-22773685-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SLC7A7 | NM_003982.4 | c.1460del | p.Cys487LeufsTer32 | frameshift_variant | 10/10 | ENST00000674313.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SLC7A7 | ENST00000674313.1 | c.1460del | p.Cys487LeufsTer32 | frameshift_variant | 10/10 | NM_003982.4 | P1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251466Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135908
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727244
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GnomAD4 genome 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lysinuric protein intolerance Pathogenic:4
| Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Cys487Leufs*32) in the SLC7A7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the SLC7A7 protein. This variant is present in population databases (rs386833809, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with lysinuric protein intolerance (PMID: 10655553). This variant is also known as 1746delG. ClinVar contains an entry for this variant (Variation ID: 56361). This variant disrupts a region of the SLC7A7 protein in which other variant(s) (p.Ser489Pro) have been observed in individuals with SLC7A7-related conditions (PMID: 12402335). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2023 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at