rs189174414

Positions:

chr11-68780734-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001876.4(CPT1A):c.1364A>C(p.Lys455Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

CPT1A
NM_001876.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.78

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-68780734-T-G is Pathogenic according to our data. Variant chr11-68780734-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189151.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.1364A>C	p.Lys455Thr	missense_variant	12/19	ENST00000265641.10	NP_001867.2	P50416-1A0A024R5F4Q8WZ48B2RAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CPT1A	ENST00000265641.10 linkuse as main transcript	c.1364A>C	p.Lys455Thr	missense_variant	12/19	1	NM_001876.4	ENSP00000265641.4	P50416-1
CPT1A	ENST00000376618.6 linkuse as main transcript	c.1364A>C	p.Lys455Thr	missense_variant	12/19	1		ENSP00000365803.2	P50416-2
CPT1A	ENST00000540367.5 linkuse as main transcript	c.1364A>C	p.Lys455Thr	missense_variant	11/18	1		ENSP00000439084.1	P50416-2
CPT1A	ENST00000539743.5 linkuse as main transcript	c.1364A>C	p.Lys455Thr	missense_variant	11/18	5		ENSP00000446108.1	P50416-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000223

AC:

AN:

251492

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135920

show subpopulations

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:

0.00194

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1461756

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00176

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000203

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000335

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2023	For these reasons, this variant has been classified as Pathogenic. 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 CPT1A protein function. ClinVar contains an entry for this variant (Variation ID: 189151). This missense change has been observed in individual(s) with CPT1A-related conditions (PMID: 21962599). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs189174414, gnomAD 0.2%). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 455 of the CPT1A protein (p.Lys455Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 02, 2021	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2023

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: 15970898, 17060594, 21962599, 17060592) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

.;.;D;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

.;D;.;D

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;H;H;H

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.7

D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.066

T;T;T;T

Polyphen

0.99

D;D;D;D

Vest4

0.98

MVP

0.99

MPC

1.4

ClinPred

0.92

GERP RS

5.0

Varity_R

0.95

gMVP

0.99

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