Submissions for variant NM_001876.4(CPT1A):c.100T>C (p.Ser34Pro)

dbSNP: rs398123653

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723488	SCV000111793	uncertain significance	not provided	2018-07-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000723488	SCV000589320	likely pathogenic	not provided	2023-02-10	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000693588	SCV000821463	pathogenic	Carnitine palmitoyl transferase 1A deficiency	2023-08-31	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000693588	SCV000894655	uncertain significance	Carnitine palmitoyl transferase 1A deficiency	2018-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407458	SCV004107766	uncertain significance	CPT1A-related condition	2023-09-20	criteria provided, single submitter	clinical testing	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.