rs80356790
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001876.4(CPT1A):c.1241C>T(p.Ala414Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 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 (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CPT1A
NM_001876.4 missense
NM_001876.4 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 9.80
Genes affected
CPT1A (HGNC:2328): (carnitine palmitoyltransferase 1A) The mitochondrial oxidation of long-chain fatty acids is initiated by the sequential action of carnitine palmitoyltransferase I (which is located in the outer membrane and is detergent-labile) and carnitine palmitoyltransferase II (which is located in the inner membrane and is detergent-stable), together with a carnitine-acylcarnitine translocase. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
?
Variant 11-68781882-G-A is Pathogenic according to our data. Variant chr11-68781882-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPT1A | NM_001876.4 | c.1241C>T | p.Ala414Val | missense_variant | 11/19 | ENST00000265641.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPT1A | ENST00000265641.10 | c.1241C>T | p.Ala414Val | missense_variant | 11/19 | 1 | NM_001876.4 | P1 | |
CPT1A | ENST00000376618.6 | c.1241C>T | p.Ala414Val | missense_variant | 11/19 | 1 | |||
CPT1A | ENST00000540367.5 | c.1241C>T | p.Ala414Val | missense_variant | 10/18 | 1 | |||
CPT1A | ENST00000539743.5 | c.1241C>T | p.Ala414Val | missense_variant | 10/18 | 5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461854Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 exome
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2
AN:
1461854
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35
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1
AN XY:
727238
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carnitine palmitoyl transferase 1A deficiency Pathogenic:3Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 22, 2024 | Variant summary: CPT1A c.1241C>T (p.Ala414Val) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR032476) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.1241C>T has been reported in the literature in individuals affected with Carnitine Palmitoyltransferase I Deficiency (Gobin_2022). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a severe decrease in catalytic activity (Gobin_2023). The following publications have been ascertained in the context of this evaluation (PMID: 12189492, 14517221). ClinVar contains an entry for this variant (Variation ID: 9065). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2021 | 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. Experimental studies have shown that this missense change affects CPT1A function (PMID: 14517221). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 9065). This missense change has been observed in individual(s) with carnitine palmitoyltransferase 1A deficiency (PMID: 12189492). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 414 of the CPT1A protein (p.Ala414Val). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 12, 2003 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of methylation at K413 (P = 0.0319);Gain of methylation at K413 (P = 0.0319);Gain of methylation at K413 (P = 0.0319);Gain of methylation at K413 (P = 0.0319);
MVP
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at