rs74315294

chr1-53202427-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 11P and 4B. PM1 PP3 PP5_Very_Strong BS2

The NM_000098.3(CPT2):c.338C>T(p.Ser113Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00167 in 1,611,988 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S113S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: CPT2 NM_000098.3 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:44 O:2
• Conservation: PhyloP100: 7.03

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 Likely_pathogenic. Variant got 7 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-53202427-C-T is Pathogenic according to our data. Variant chr1-53202427-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-53202427-C-T is described in Lovd as [Pathogenic]. Variant chr1-53202427-C-T is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.338C>T	p.Ser113Leu	missense_variant, splice_region_variant	3/5	ENST00000371486.4
CPT2	NM_001330589.2	c.338C>T	p.Ser113Leu	missense_variant, splice_region_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.338C>T	p.Ser113Leu	missense_variant, splice_region_variant	3/5	1	NM_000098.3	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00139 AC: 350 AN: 251450 Hom.: 4 AF XY: 0.00141 AC XY: 192 AN XY: 135902

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00724

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00171 AC: 2496 AN: 1459714 Hom.: 8 Cov.: 29 AF XY: 0.00168 AC XY: 1221 AN XY: 726314

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00923

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74458

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00195 Hom.: 3

Bravo AF: 0.00135

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00127 AC: 154

EpiCase AF: 0.00224

EpiControl AF: 0.00219

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:44 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 08, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1999	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Nov 08, 2023	The CPT2 c.338C>T (p.Ser113Leu) variant is the most common variant in individuals affected with carnintine palmitoyl transferase II deficiency, the mild myopathic form and is reported to segregate with disease. Of those individuals, approximately 18 were compound heterozygous and 38 homozygous. At least 21 heterozygous carriers have also been described with a subset that are clinically symptomatic with muscle CPT activity 39-45% of normal reference (Joshi PR et al., PMID: 23184072; Kaufmann P et al., PMID: 9309694; Taggart RT et al., PMID: 10090476; Taroni F et al., PMID: 8358442). Functional studies show abnormal regulation of the enzyme and thermal instability, indicating that this variant impacts protein function (Taroni F et al., PMID: 8358442; Motlagh L et al., PMID: 26477380). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.75% in the Ashkenazi Jewish population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to CPT2 function. This variant has been reported in the ClinVar database as a pathogenic variant by 35 submitters and likely pathogenic by 3 submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 09, 2022	This CPT2 variant (rs74315294) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the European (non-Finnish) subpopulation (gnomAD: 238/129144 alleles; 0.18%, 1 homozygote). However, the minor allele frequency is low enough to be consistent with a recessive carrier frequency. This variant, c.338C>T (p.Ser113Leu), has been reported in ClinVar, and is the most common pathogenic variant associated with late-onset (myopathic) carnitine palmitoyltransferase deficiency in individuals of European ancestry; most of the patients reported to date were homozygous for this variant. Experimental studies demonstrate that this missense variant significantly reduces enzyme activity. We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 27, 2020	This sequence change is predicted to replace serine with leucine at codon 113 of the CPT2 protein (p.(Ser113Leu)). The serine residue is highly conserved (100 vertebrates, UCSC), and is located in the mitochondrial matrix region of carnitine O-palmitoyltransferase 2 (UniProt). There is a large physicochemical difference between serine and leucine. The variant is present in a large population cohort at a frequency of 0.14% (rs74315294, 393/282,834 alleles, 4 homozygotes in gnomAD v2.1). The variant is the most commonly occurring pathogenic variant in CPT2 associated with the myopathic form CPT II deficiency (PMID: 20301431). It has been identified in the homozygous state and with a second pathogenic allele in multiple individuals diagnosed with recurrent myoglobinuria/rhabdomyolysis (PM3_VeryStrong; for example PMID: 8358442, 12707442, 20810031). Segregation of the homozygous variant has been reported in at least two families with the phenotype ranging from reduced tolerance to exercise to recurrent rhabdomyolysis (PP1_Strong; PMID: 8786066, 20810031). Homozygous cases are reported with significantly reduced CPT II enzyme activity and slightly reduced or normal long-chain fatty acid oxidation levels in tissues, and markedly reduced CPT II activity is also demonstrated in in vitro expression studies (PP4, PS3_Supporting; PMID: 8358442, 8651281). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	May 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neonatal, infantile and stress-induced myopathic CPT II deficiency. (I) 0106 - This gene is associated with autosomal recessive disease. This gene is generally considered to be associated with an autosomal recessive condition, but some cases of manifesting carriers have been reported for the myopathic form of CPT II deficiency (PMID: 32295037). (I) 0115 - Variants in this gene are known to have variable expressivity. The myopathic form of this condition can manifest from infancy to adulthood and variable onset, frequency, and severity of symptoms have been reported (PMID: 32295037). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (385 heterozygotes, 4 homozygotes) and is enriched in the Ashkenazi Jewish sub-population. (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Choline/Carnitine o-acyltransferase domain (NCBI domain). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as the most common cause of the myopathic form of CPT II deficiency in individuals of European ancestry (ClinVar, PMID: 8358442, PMID: 21913903, PMID: 32295037). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2019	The best available variant frequency is 1-3 times higher than the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant appears to segregate with disease in at least one family. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	Most common CPT2 pathogenic variant found in approximately 60% of mutant alleles in European patients with the adult myopathic form of CPT2 deficiency (Bonnefont et al., 2004); Children who are compound heterozygotes with S113L have also been reported, presenting with myopathic features or an intermediate phenotype (Sigauke et al., 2003); Published functional studies demonstrate a damaging effect (Taroni et al. 1993; Motlagh et al. 2015; Motlagh et al. 2016); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 26477380, 15776096, 17936304, 30149802, 30609409, 15363638, 27123472, 8358442, 9600456, 23184072, 11595519, 21228398, 22975760, 24563797, 25333069, 27034144, 28054946, 15642848, 12707442, 26990548, 29744303, 27067077, 29478820, 28779239, 31191612, 31517061, 31407473, 32272925, 31980526, 34426522, 16225172, 31589614, 8786066, 9309694, 32528171, 32140910, 33815142, 14615409) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 30, 2022	The CPT2 c.338C>T; p.Ser113Leu variant (rs74315294), is reported in the homozygous and compound heterozygous state in the literature as the most common variant in individuals affected with the adult myopathic form of carnitine palmitoyltransferase II deficiency (Avila-Smirnow 2018, Balasubramanian 2018, Edmondson 2017, Fontaine 2018, Joshi 2012, Kottlors 2001, Taroni 1993, Vavlukis 2014, Vivante 2017, Wataya 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 8953), and is found in the general population with an overall allele frequency of 0.14% (393/282,834 alleles, including 4 homozygotes) in the Genome Aggregation Database. The serine at codon 338 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.887). Functional analyses of the variant protein shows a reduction in stability leading to decreased enzyme activity (Motlagh 2016a, Motlagh 2016b, Taroni 1993). Based on available information, the p.Ser113Leu variant is considered to be pathogenic. References: Avila-Smirnow D et al. Carnitine palmitoyltransferase type 2 deficiency: novel mutation in a Native South American family with whole-body muscle magnetic resonance imaging findings: two case reports. J Med Case Rep. 2018 Aug 28;12(1):249. PMID: 30149802. Balasubramanian M et al. Recurrent rhabdomyolysis caused by carnitine palmitoyltransferase II deficiency, common but under-recognised: Lessons to be learnt. Mol Genet Metab Rep. 2018 Mar 6;15:69-70. PMID: 29744303. Edmondson AC et al. Missed Newborn Screening Case of Carnitine Palmitoyltransferase-II Deficiency. JIMD Rep. 2017;33:93-97. PMID: 27067077. Fontaine M et al. Fluxomic assay-assisted diagnosis orientation in a cohort of 11 patients with myopathic form of CPT2 deficiency. Mol Genet Metab. 2018 Apr;123(4):441-448. PMID: 29478820. Joshi PR et al. Clinically symptomatic heterozygous carnitine palmitoyltransferase II (CPT II) deficiency. Wien Klin Wochenschr. 2012 Dec;124(23-24):851-4. PMID: 23184072. Kottlors M et al. Valproic acid triggers acute rhabdomyolysis in a patient with carnitine palmitoyltransferase type II deficiency. Neuromuscul Disord. 2001 Nov;11(8):757-9. PMID: 11595519. Motlagh L et al. Malony-CoA inhibits the S113L variant of carnitine-palmitoyltransferase II. Biochim Biophys Acta. 2016 Jan;1861(1):34-40. PMID: 26477380. Motlagh L et al. Stabilization of the thermolabile variant S113L of carnitine palmitoyltransferase II. Neurol Genet. 2016 Feb 25;2(2):e53. PMID: 27123472. Taroni F et al. Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet. 1993 Jul;4(3):314-20. PMID: 8358442. Vavlukis M et al. Rhabdomyolysis and Cardiomyopathy in a 20-Year-Old Patient with CPT II Deficiency. Case Rep Genet. 2014;2014:496410. PMID: 24563797. Vivante A et al. Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases. Pediatr Nephrol. 2017 Dec;32(12):2273-2282. PMID: 28779239. Wataya K et al. Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes. Hum Mutat. 1998;11(5):377-86. PMID: 9600456. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CPT2: PM3, PS4:Moderate, PM2:Supporting, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 10, 2020	PS3, PS4, PM2, PP5 -

Carnitine palmitoyltransferase II deficiency Pathogenic:7 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 113 of the CPT2 protein (p.Ser113Leu). This variant is present in population databases (rs74315294, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with carnitine palmitoyltransferase II deficiency (PMID: 8786066, 9309694, 10090476, 10398215, 12673791, 12707442, 15642848, 15776096, 17936304, 21913903). It is commonly reported in individuals of European ancestry (PMID: 8786066, 9309694, 10090476, 10398215, 12673791, 12707442, 15642848, 15776096, 17936304, 21913903). ClinVar contains an entry for this variant (Variation ID: 8953). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CPT2 function (PMID: 2647738, 8358442, 27123472). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CPT2 c.338C>T (p.Ser113Leu) missense variant is the most commonly occurring pathogenic variant in the CPT2 gene, accounting for approximately 60% of disease alleles (Wieser et al. 2014). Across a small selection of the available literature, the p.Ser113Leu variant was identified in a total of 77 individuals with carnitine palmitoyltransferase II deficiency, including 38 homozygotes, 18 compound heterozygotes, and 21 heterozygotes in whom a second variant was not reported (Taroni et al. 1993; Bonnefont et al. 1996; Martin et al. 1999; Anichini et al. 2011; Fanin et al. 2012; Shima et al. 2016). The variant was also found in nine unaffected heterozygous carriers (Martin et al. 1999). The p.Ser113Leu variant was absent from 64 controls but is reported at a frequency of 0.00201 in the European (non-Finnish) population of the Exome Aggregation Consortium. Taroni et al. (1993) demonstrated that the p.Ser113Leu variant displayed significantly reduced CPT II activity but similar enzyme synthesis as compared to wild type when transiently expressed in COS1 cells. Additionally, steady-state levels of CPT II from lymphoblasts from an individual homozygous for the p.Ser113Leu variant were significantly decreased as compared to control cells, though normal biosynthesis of CPT II was observed. Bonnefont et al. (1996) showed a reduction to 20% of wild type of residual CPT II activity in fibroblasts from an individual homozygous for the p.Ser113Leu variant. Based on the collective evidence, the p.Ser113Leu variant is classified as pathogenic for carnitine palmitoyltransferase II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported most recently on 11-25-2015 by Lab or GTR ID 500068. The variant was also interpretted as Pathogenic and reported on 11/17/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000098.2:c.338C>T in the CPT2 gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Ser113Leu (NM_000098.2:c.338C>T) variant has been observed to segregate with disease in one family with three affected individuals and two unaffected individuals (PMID: 8786066). Martin MA et al performed molecular analysis in a group of 14 Spanish patients with CPT II deficiency from ten unrelated families. The S113L mutation was observed in 8 of the 14 patients studied. Seven patients were homozygous for the mutation (PMID: 10398215). In addition, Anichini A et al reported that p.Ser113Leu was identified in five homozygote patients and in compound heterozygosity in five cases: c.338C>T (p.Ser113Leu)/c.1724T>C (p.Leu575Pro); c.338C>T (p.Ser113Leu)/c.1547T>C (p.Phe516Ser); c.338C>T (p.Ser113Leu) c.1348A>T (p.Arg450Stop); c.338C>T (p.Ser113Leu)/c.1932insA (p.E645RfsX4); c.338C>T (p.Ser113Leu)/c.1239G>A (p.Gln413Gln) (PMID: 20810031). Functional analysis demonstrates that the c.338C>T variant is associated with a significant reduction in enzyme activity (PMID:8358442). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP1_Moderate; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 30, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 02, 2014	The p.Ser113Leu variant in CPT2 is the most common variant associated with late- onset carnitine palmitoyltransferase deficiency (myopathic form); most of the pa tients reported to date (>14) were homozygous (Taroni 1993, Bonnefont 1996, Mart in 1999). The p.Ser113Leu variant has been identified in 0.2% (134/66568) of Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs74315294). Although this variant has been seen in the gener al population, its frequency is low enough to be consistent with a recessive car rier frequency. Biochemical characterization and in vitro functional studies als o provide evidence that the p.Ser113Leu variant may impact protein function (Tar oni 1993, Bonnefont 1996). In summary, this variant meets criteria to be classif ied as pathogenic for carnitine palmitoyltransferase II deficiency in an autosom al recessive manner. It should be noted that a few heterozygous carriers of this variant have been reported with mild symptoms (Taggert 1999, Kaufmann 1997). -

Carnitine palmitoyl transferase II deficiency, severe infantile form Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a frameshift mutation in a 1-year-old female with IUGR, global delays, spastic tetraparesis, brain calcifications and leukomalacia, and a similarly affected brother (who was a single heterozygote; did not carry the frameshift mutation). Heterozygotes are expected to be asymptomatic carriers. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.139%). Protein truncation variants are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 26477380, 27123472, 8358442). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.34). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008953 / PMID: 8358442). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11994355, 14615409, 20810031). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Dec 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000098.2(CPT2):c.338C>T(S113L) is classified as pathogenic in the context of carnitine palmitoyltransferase II deficiency. Please note that the S113L variant is associated with the myopathic form of carnitine palmitoyltransferase II deficiency. Disease phenotype is dependent on, but not necessarily predicted by, the combination of variants inherited. Sources cited for classification include the following: PMID 21913903, 16996287, 15642848 and 835844. Classification of NM_000098.2(CPT2):c.338C>T(S113L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 30, 2022	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -

Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jan 05, 2015

- -

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

May 18, 2017

- -

Rhabdomyolysis Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Aug 05, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2020

The c.338C>T (p.S113L) alteration is located in exon 3 (coding exon 3) of the CPT2 gene. This alteration results from a C to T substitution at nucleotide position 338, causing the serine (S) at amino acid position 113 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the CPT2 c.338C>T alteration was observed in 0.14% (393/282834) of total alleles studied, with a frequency of 0.75% (78/10370) in the Ashkenazi Jewish subpopulation. This variant is a common mutation for the myopathy form of carnitine palmitoyltransferase 2 (CPTII) deficiency and has been reported in numerous homozygous and compound heterozygous individuals (Vladutiu, 2002; Taroni, 1993; Martín, 2000; Taggart, 1999; Handig, 1996). This amino acid position is well conserved in available vertebrate species. COS1 cells with this variant demonstrated reduced activity compared to wild type (Taroni, 1993). The p.S113L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;.;.;T;T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.041	T;T;T;T;T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	D;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.85
MVP		1.0
MPC		0.51
ClinPred		0.50	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.020		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: rs74315294; hg19: chr1-53668099; COSMIC: COSV65186978;