rs386134218
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_003060.4(SLC22A5):āc.1340A>Gā(p.Tyr447Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_003060.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727228
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:6
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Variant summary: SLC22A5 c.1340A>G (p.Tyr447Cys) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.1340A>G has been reported in the literature as a biallelic genotype in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Rahbeeni_2002, Dobrowolski_2005, Rose_2012, Frigeni_2017). These data indicate that the variant is likely to be associated with disease. Functional evidence using transfected CHO cells showed that the variant had similar carnitine transport activity as untransfected cells (0%), which may in part be due to mislocalization of the protein: the variant protein did not traffic normally to the cell surface, and was retained within the cytoplasm (Amat di San Filippo_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16652335, 15714519, 28841266, 12408185, 21922592). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the SLC22A5 protein (p.Tyr447Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 12408185, 28841266). ClinVar contains an entry for this variant (Variation ID: 25418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 16652335). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Transfection of Y447C into CHO cells showed carnitine and tetraethylammonium transport comparable to that in untransfected cells (Amat di San Filippo et al., 2004); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12408185, 22555822, 14665638, 16652335, 21922592, 28841266) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at