rs80356779

Positions:

chr11-68780662-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_001876.4(CPT1A):c.1436C>T(p.Pro479Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,156 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P479Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 3 hom. )

Consequence

CPT1A
NM_001876.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10U:1B:1O:1

Conservation

PhyloP100: 9.70

Variant links:

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]

CPT1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-68780662-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 11-68780662-G-A is Pathogenic according to our data. Variant chr11-68780662-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT1A	NM_001876.4 linkuse as main transcript	c.1436C>T	p.Pro479Leu	missense_variant	12/19	ENST00000265641.10	NP_001867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT1A	ENST00000265641.10 linkuse as main transcript	c.1436C>T	p.Pro479Leu	missense_variant	12/19	1	NM_001876.4	ENSP00000265641	P1	P50416-1
CPT1A	ENST00000376618.6 linkuse as main transcript	c.1436C>T	p.Pro479Leu	missense_variant	12/19	1		ENSP00000365803		P50416-2
CPT1A	ENST00000540367.5 linkuse as main transcript	c.1436C>T	p.Pro479Leu	missense_variant	11/18	1		ENSP00000439084		P50416-2
CPT1A	ENST00000539743.5 linkuse as main transcript	c.1436C>T	p.Pro479Leu	missense_variant	11/18	5		ENSP00000446108	P1	P50416-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251490

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:1Benign:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency

Pathogenic:5Uncertain:1Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	The p.Pro479Leu variant results in high residual enzyme activity and a detectable protein of normal size and amount on western blot analysis. It is believed that the product of the p.Pro479Leu allele affects malonyl-CoA interaction with CPT1A. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2024	Variant summary: CPT1A c.1436C>T (p.Pro479Leu) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) 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 3.2e-05 in 251490 control chromosomes (gnomAD), however the variant was reported at a much higher frequency in certain Northern populations (e.g. in the Inuit), and it was reported to be the major allele in Greenlanders, with a frequency of 0.73 (Rajakumar_2009), which suggests that the variant is a benign polymorphism. On the other hand, a clinical trial demonstrated that children homozygous for P479L had impaired fasting tolerance, resulting in hypoketotic hypoglycemia in response to prolonged fasting, though not all subjects developed hypoglycemia at the end of the testing period (Gillingham_2011). In addition, the variant was reported in homozygous infants affected with neonatal hypoglycemia, however, not all homozygotes developed clinical symptoms (Greenberg_2009). Additionally, a large cohort of Inuit newborns, found that neonatal hypoglycemia (NH) was reported in 22% of P479L homozygotes, and 19.8% of P479L heterozygotes, while only in 4.8% of non-carrier newborns (Collins_2020). Some studies also proposed that the variant might be associated with elevated infant mortality rates in populations where the variant is frequent (Greenberg_2009, Collins_2011, Gessner_2016). These data indicate that the variant is likely to be associated with an elevated risk of disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in partially decreased enzymatic activity, with a significant decrease in sensitivity to inhibition by malonyl-CoA, which might somewhat ameliorate the decreased catalytic capacity (Brown_2001); in addition, fibroblasts from several homozygous individuals demonstrated reduced enzyme activity (e.g. Brown_2001, Greenberg_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19217814, 11441142, 20696606, 21763168, 32088118, 19181627, 32561900, 26820065, 34131458). ClinVar contains an entry for this variant (Variation ID: 65644). Based on the evidence outlined above, the variant seems to cause a partial loss of enzyme activity, resulting in a hypomorphic allele with reduced penetrance, and therefore was classified as pathogenic. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jul 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 479 of the CPT1A protein (p.Pro479Leu). This variant is present in population databases (rs80356779, gnomAD 0.006%). This missense change has been observed in individuals with CPT1 deficiency (PMID: 19217814, 20301700, 20696606). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65644). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CPT1A protein function. Experimental studies have shown that this missense change affects CPT1A function (PMID: 11441142). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	Common variant in individuals with CPT1A deficiency from the Inuit and Alaska Native populations (PMID: 20301700); High frequency of P479L homozygotes in certain populations indicates that under normal circumstances individuals with this genotype are rarely symptomatic. However, children homozygous for P479L have shown abnormal metabolic response to prolonged fasting and may have an increased risk for infant mortality (PMID: 21763168, 20696606, 23090344); Expression of P479L in COS cells found that it is associated with reduced CPT1A enzyme activity compared to wild type (PMID: 11441142); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26010953, 23757202, 20696606, 27341449, 35944424, 28125087, 25449608, 22045927, 19217814, 20843525, 19181627, 23090344, 27127449, 26820065, 21763168, 28611031, 30996616, 32561900, 34295859, 20301700, 11441142) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2014	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2021

The c.1436C>T (p.P479L) alteration is located in exon 12 (coding exon 11) of the CPT1A gene. This alteration results from a C to T substitution at nucleotide position 1436, causing the proline (P) at amino acid position 479 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (9/282900) total alleles studied. This mutation is a prevalent mutation in Inuit and Alaska Native populations, commonly identified in the homozygous state (Brown, 2001; Rajakumar, 2009; Greenberg, 2009; Collins, 2010; Clemente, 2014). Some homozygous infants demonstrate impaired fasting intolerance (Gillingham, 2011) and increased risk of infant mortality (Gessner, 2016). CPT1 activity in fibroblasts from homozygous individuals demonstrated reduced activity compared to controls between 2-16% (Brown, 2001; Greenberg, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

CPT1A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2024

The CPT1A c.1436C>T variant is predicted to result in the amino acid substitution p.Pro479Leu. This variant has been reported at a high frequency in Alaskan native and other arctic populations (Greenberg et al. 2009. PubMed ID: 19217814; Clemente et al. 2014. PubMed ID: 25449608). The p.Pro479Leu amino acid substitution has been shown to reduce enzyme activity to ~20% of normal (Brown et al. 2001, PubMed ID: 11441142). Patients with carnitine palmitoyltransferase (CPT) 1A deficiency due to homozygosity for the c.1436C>T variant tend to be clinically unaffected or present with a relatively mild clinical course that primarily includes impaired fasting tolerance and potentially hypoketotic hypoglycemia (Greenberg et al. 2009, PubMed ID: 19217814; Gillingham et al. 2011, PubMed ID: 21763168; Clemente et al. 2014, PubMed ID: 25449608). Affected females have been reported to develop maternal acute fatty liver of pregnancy (AFLP) (Greenberg et al. 2009, PubMed ID: 19217814). This variant has been associated with increased risk for infant mortality (Gessner et al. 2010. PubMed ID: 20937660). Taken together, we interpret this variant as pathogenic. -

CPT1A ARCTIC VARIANT

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

CARNITINE PALMITOYLTRANSFERASE IA POLYMORPHISM

Benign:1

Benign, flagged submission

literature only

OMIM

Jul 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;.;D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;.;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.3

M;M;M;M

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.3

D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.99

MutPred

0.89

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.98

MPC

0.79

ClinPred

0.90

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over