Submissions for variant NM_001876.4(CPT1A):c.1436C>T (p.Pro479Leu)

gnomAD frequency: 0.00006  dbSNP: rs80356779

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079911	SCV000225586	pathogenic	not provided	2014-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000079911	SCV000321521	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	Common variant in individuals with CPT1A deficiency from the Inuit and Alaska Native populations (Bennett, M., 2009); Expression of P479L in COS cells found that it is associated with reduced CPT1A enzyme activity compared to wild type (Brown et al., 2001); 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 (Gillingham et al., 2011; Collins et al., 2010; Sinclair et al., 2012); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32561900, 30996616, 28125087, 28611031, 21763168, 26820065, 27127449, 27341449, 23090344, 20696606, 23757202, 19181627, 20843525, 26010953, 11441142, 19217814, 22045927, 25449608)
Invitae	RCV000551382	SCV000638094	pathogenic	Carnitine palmitoyl transferase 1A deficiency	2024-01-20	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000551382	SCV002019718	pathogenic	Carnitine palmitoyl transferase 1A deficiency	2022-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000551382	SCV002555789	pathogenic	Carnitine palmitoyl transferase 1A deficiency	2022-06-09	criteria provided, single submitter	clinical testing	Variant summary: CPT1A c.1436C>T (p.Pro479Leu; aka. the 'Arctic variant') results in a non-conservative amino acid change in 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 (18h), though not all subjects developed hypoglycemia at the end of the testing period (Gillingham_2011). In addition, the variant was reported in homozygous form in infants affected with neonatal hypoglycemia, however, not all homozygotes developed clinical symptoms (Greenberg_2009). A recent study examining 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). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as pathogenic (n=4) or VUS (n=1). 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.
PreventionGenetics, part of Exact Sciences	RCV003415824	SCV004107244	pathogenic	CPT1A-related disorder	2023-03-27	criteria provided, single submitter	clinical testing	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). Taken together, we interpret this variant as pathogenic.
Baylor Genetics	RCV000551382	SCV004211017	uncertain significance	Carnitine palmitoyl transferase 1A deficiency	2022-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018983	SCV004850231	pathogenic	Inborn genetic diseases	2021-08-25	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV000551382	SCV000086856	not provided	Carnitine palmitoyl transferase 1A deficiency		no assertion provided	literature only	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.
OMIM	RCV000714476	SCV000845174	benign	CARNITINE PALMITOYLTRANSFERASE IA POLYMORPHISM	2001-07-01	no assertion criteria provided	literature only
OMIM	RCV000714477	SCV000845175	pathogenic	CPT1A ARCTIC VARIANT	2001-07-01	no assertion criteria provided	literature only
Counsyl	RCV000551382	SCV001132373	uncertain significance	Carnitine palmitoyl transferase 1A deficiency	2019-07-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000551382	SCV001456362	pathogenic	Carnitine palmitoyl transferase 1A deficiency	2020-09-16	no assertion criteria provided	clinical testing