rs28936375

chr1-53197092-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP3 PP5_Very_Strong BP4

The NM_000098.3(CPT2):c.149C>A(p.Pro50His) variant causes a missense change. The variant allele was found at a frequency of 0.000331 in 1,538,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P50S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 4.63

Genes affected

CPT2 (HGNC:2330): (carnitine palmitoyltransferase 2) The protein encoded by this gene is a nuclear protein which is transported to the mitochondrial inner membrane. Together with carnitine palmitoyltransferase I, the encoded protein oxidizes long-chain fatty acids in the mitochondria. Defects in this gene are associated with mitochondrial long-chain fatty-acid (LCFA) oxidation disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a topological_domain Mitochondrial matrix (size 152) in uniprot entity CPT2_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) in NM_000098.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-53197091-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2078263.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-53197092-C-A is Pathogenic according to our data. Variant chr1-53197092-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.016327322).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.149C>A	p.Pro50His	missense_variant	1/5	ENST00000371486.4
CPT2	NM_001330589.2	c.149C>A	p.Pro50His	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.149C>A	p.Pro50His	missense_variant	1/5	1	NM_000098.3	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000173 AC: 23 AN: 132920 Hom.: 0 AF XY: 0.000207 AC XY: 15 AN XY: 72450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.000246

GnomAD4 exome AF: 0.000345 AC: 478 AN: 1386116 Hom.: 0 Cov.: 30 AF XY: 0.000319 AC XY: 218 AN XY: 684186

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00216

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.000294

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74278

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000146 AC: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2023	The p.Pro50His variant in CPT2 has been reported in the homozygous state in least 2 individuals and in the compound heterozygous state in at least 5 individuals with CPTII deficiency, at least 2 of whom were found to have low CPT II activity and segregated with disease in 1 affected relative. Most of these individuals had the myopathic form with juvenile to adult onset, however one individual who had a loss of function variant on the other copy of the CPT2 gene had infantile onset (Verderio 1995 PMID: 7711730, Taggart 1999 PMID: 10090476, Vladutiu 2002 PMID: 12410208, Wieser 2003 PMID: 12707442, Orngreen 2005 PMID: 15622536, Isackson 2006 PMID: 16996287, Corti 2008 PMID: 17936304). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 8954) and has been identified in 0.1% (15/10614) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant significantly affects the CPT II catalytic activity (Verderio 1995 PMID: 7711730) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CPTII deficiency though it should we noted that this variant typically causes the milder myopathic form; however, when found with a loss of function variant, it can cause more severe disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting, PP4. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2017	Variant summary: The CPT2 c.149C>A (p.Pro50His) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. This variant was found in 2/11728 control chromosomes at a frequency of 0.0001705, which does not exceed the estimated maximal expected allele frequency of a pathogenic CPT2 variant (0.0015811). Multiple publications cite the variant in compound heterozygote affected individuals, which were found to have low CPT II activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 50 of the CPT2 protein (p.Pro50His). This variant is present in population databases (rs28936375, gnomAD 0.2%). This missense change has been observed in individual(s) with CPT2 deficiency (PMID: 7711730, 10090476, 12410208, 12707442, 16996287, 17936304). 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: 8954). 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 CPT2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 7711730). For these reasons, this variant has been classified as Pathogenic. -

Carnitine palmitoyl transferase II deficiency, severe infantile form Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 02, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 11, 2023	This sequence change in CPT2 is predicted to replace proline with histidine at codon 50, p.(Pro50His). The proline residue is highly conserved (65/65 vertebrates, UCSC), and is located in the carnitine o-acyltransferase domain. There is a moderate physicochemical difference between proline and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.16% (17/10,486 alleles) in the Finnish population. However, the highest continental population minor allele frequency is 0.02% (11/64,794 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is one of the most common pathogenic variants associated with the myopathic form of CPTII deficiency identified in Europeans (PMID: 20301431). It has been detected in multiple individuals CPTII deficiency diagnosed on muscle biopsy in the homozygous state or compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 7711730, 12673791, 12707442, 16996287). In vitro enzyme assays demonstrated the variant has reduced enzyme function at different temperatures indicating that this variant impacts protein function (PMID: 34063237). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP3, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Program, Stanford Medicine	Jun 01, 2021	• The p.Pro50His variant in the CPT2 gene has been previously reported in the homozygous or compound heterozygous state in many individuals affected with CPT II deficiency, and is recognized as one of the most common disease-causing variants identified in individuals with the myopathic presentation of disease (Taggart et al., 1999; Wieser et al., 2003; Ørngreen et al., 2005; Isackson et al., 2006). • The p.Pro50His variant is typically associated with the later-onset myopathic form of disease, but has been reported in association with the severe infantile form when compound heterozygous with a truncating variant (Vladutiu et al., 2002). • Heterozygous carriers of the p.Pro50His variant have been rarely reported to be clinically affected with adult- onset myopathy (Isackson et al., 2006). • • • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Pro50His variant as pathogenic for autosomal recessive CPT II deficiency based on the information above. [ACMG evidence codes used: PM3_Very Strong; PM2; PS3_Supporting; PP3]This variant has been identified in 17/10,486 European (Finnish) chromosomes (32/164,218 chromosomesoverall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant hasbeen seen in the general population, its frequency is low enough to be consistent with a recessive carrierfrequency.Functional studies of the p.Pro50His variant are supportive of a deleterious effect to the protein and haveshown decreased stability of the mutant CPT II protein (Verderio et al., 1995) -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2022	Common CPT2 pathogenic variant found in approximately 6.5% of mutant alleles in patients with the adult myopathic form of carnitine palmitoyltransferase II (CPT2) deficiency (Bonnefont et al., 2004); Published functional studies in found P50H is associated with significantly reduced carnitine palmitoyltransferase II enzyme activity compared to wild type (Wataya et al. 1998); 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: 10090476, 12707442, 15363638, 22975760, 7711730, 31589614, 12410208, 15622536, 20301431, 31541997, 12673791, 17936304, 16996287, 33673806, 9600456) -

Carnitine palmitoyl transferase II deficiency, myopathic form;C1833511:Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form;C3280160:Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 27, 2022

- -

Arthritis;C0013363:Abnormal autonomic nervous system physiology;C0030312:Pancytopenia;C0039239:Sinus tachycardia;C0150055:Chronic pain;C0162323:Polyarticular arthritis;C1836923:Gastrointestinal dysmotility;C1881170:Inappropriate sinus tachycardia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;T;T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D;D;D;T;D
MetaRNN	Benign	0.016	T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.8	D;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;.;.;.;.
Sift4G	Uncertain	0.0050	D;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.73
MutPred		0.92		Loss of glycosylation at P50 (P = 0.0582);Loss of glycosylation at P50 (P = 0.0582);Loss of glycosylation at P50 (P = 0.0582);Loss of glycosylation at P50 (P = 0.0582);Loss of glycosylation at P50 (P = 0.0582);Loss of glycosylation at P50 (P = 0.0582);
MVP		1.0
MPC		0.59
ClinPred		0.54	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.97
gMVP		0.81

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

Other links and lift over

dbSNP: rs28936375; hg19: chr1-53662764; COSMIC: COSV104682695; COSMIC: COSV104682695;