rs185551386
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The ENST00000245407.8(SLC22A5):c.680G>A(p.Arg227His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,154 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227C) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000245407.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.680G>A | p.Arg227His | missense_variant | 4/10 | ENST00000245407.8 | NP_003051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.680G>A | p.Arg227His | missense_variant | 4/10 | 1 | NM_003060.4 | ENSP00000245407 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000596 AC: 15AN: 251480Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135916
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461790Hom.: 1 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727210
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74500
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 06, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2024 | Variant summary: SLC22A5 c.680G>A (p.Arg227His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (6e-05 vs 0.0046), allowing no conclusion about variant significance. c.680G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Li_2010, Tong_2018, Yang_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 20574985, 28841266, 29581464, 34249102). ClinVar contains an entry for this variant (Variation ID: 378583). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 13, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 227 of the SLC22A5 protein (p.Arg227His). This variant is present in population databases (rs185551386, gnomAD 0.03%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985, 26828774; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 378583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 25, 2021 | The SLC22A5 c.680G>A; p.Arg227His variant (rs185551386) is reported in the literature in multiple individuals with primary carnitine deficiency (Guo 2018, Li 2010, Tong 2018). Functional analyses of the variant protein show significantly decreased carnitine transport activity (Frigeni 2017). This variant is also reported in ClinVar (Variation ID: 378583). This variant is found in the Latino population with an allele frequency of 0.03% (12/34592 alleles) in the Genome Aggregation Database. The arginine at codon 227 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.885). Based on available information, this variant is considered to be pathogenic. References: Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Guo K et al. Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population. Front Genet. 2018 Apr 20;9:122. Li FY et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010 Aug;31(8):E1632-51. Tong W et al. Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea. Sci Rep. 2018 Mar 26;8(1):5214. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2023 | Published functional studies demonstrate the R227H variant significantly reduces carnitine transport compared to wild-type (Frigeni et al., 2017); 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: 34637945, 20574985, 26828774, 29581464, 29731766, 32778825, 28841266) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at