rs398123653

Positions:

• chr11-68815375-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The ENST00000265641.10(CPT1A):​c.100T>C​(p.Ser34Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S34F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A ENST00000265641.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.24

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-68815374-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1014808.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 11-68815375-A-G is Pathogenic according to our data. Variant chr11-68815375-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93971.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT1A	NM_001876.4	c.100T>C	p.Ser34Pro	missense_variant	2/19	ENST00000265641.10	NP_001867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT1A	ENST00000265641.10	c.100T>C	p.Ser34Pro	missense_variant	2/19	1	NM_001876.4	ENSP00000265641	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2023	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 34 of the CPT1A protein (p.Ser34Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CPT1A-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 93971). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Ser34 amino acid residue in CPT1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35822099) -

CPT1A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2023

The CPT1A c.100T>C variant is predicted to result in the amino acid substitution p.Ser34Pro. This variant has been detected in the homozygous state in multiple individuals through expanded metabolic screening (EMS), including in three unaffected homozygous adults ascertained during family follow up studies (Table 1, Bernhardt et al. 2022. PubMed ID: 35822099). In the 22 cases described, none were reported to have episodes of significant metabolic decompensation (age range 5 weeks to 33 years), and for 10 cases no dietary management was included as part of treatment. In vitro functional study of cells from an unaffected homozygous individual showed residual CPT1A enzyme activity at ~26% of controls (Bernhardt et al. 2022. PubMed ID: 35822099). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) but is predicted to be common in the Micronesian population based on the number of homozygous individuals detected through EMS (Bernhardt et al. 2022. PubMed ID: 35822099). Although we suspect this variant is likely benign, without formal fasting studies it is unclear if this variant could result in mild clinical consequences. At this time, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;D;D;D;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	.;T;.;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.9	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.066	T;T;D;D;D;D;D
Sift4G	Uncertain	0.037	D;D;D;D;.;.;.
Polyphen		0.33	B;B;B;B;.;.;.
Vest4		0.51
MutPred		0.59		Loss of MoRF binding (P = 0.0609);Loss of MoRF binding (P = 0.0609);Loss of MoRF binding (P = 0.0609);Loss of MoRF binding (P = 0.0609);Loss of MoRF binding (P = 0.0609);Loss of MoRF binding (P = 0.0609);Loss of MoRF binding (P = 0.0609);
MVP		0.90
MPC		0.70
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.71
gMVP		0.96

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: rs398123653; hg19: chr11-68582843;