NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Mar 25, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000020069.31

Allele description [Variation Report for NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)]

NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)

HGVS:

NC_000017.11:g.7223687C>T
NG_007975.1:g.8854C>T
NG_008391.2:g.1364G>A
NG_033038.1:g.15858G>A
NM_000018.4:c.1226C>TMANE SELECT
NM_001033859.3:c.1160C>T
NM_001270447.2:c.1295C>T
NM_001270448.2:c.998C>T
NP_000009.1:p.Thr409Met
NP_001029031.1:p.Thr387Met
NP_001257376.1:p.Thr432Met
NP_001257377.1:p.Thr333Met
NP_001257377.1:p.Thr333Met
NC_000017.10:g.7127006C>T
NM_000018.2:c.1226C>T
NM_000018.3:c.1226C>T
NM_001270448.1:c.998C>T

Protein change:

T333M

Links:

dbSNP: rs113994169

NCBI 1000 Genomes Browser:

rs113994169

Molecular consequence:

NM_000018.4:c.1226C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1160C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1295C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.998C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000654921	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31031081, 26743058, 24503138, 28492532
SCV000883345	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Mar 15, 2023)	germline	clinical testing	Citation Link,
SCV001365207	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24503138, 25741868
SCV001459252	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002766631	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24503138, 26743058, 31031081, 35267200, 35400565, 25741868
SCV003822474	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004214095	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening.

Merritt JL 2nd, Vedal S, Abdenur JE, Au SM, Barshop BA, Feuchtbaum L, Harding CO, Hermerath C, Lorey F, Sesser DE, Thompson JD, Yu A.

Mol Genet Metab. 2014 Apr;111(4):484-92. doi: 10.1016/j.ymgme.2014.01.009. Epub 2014 Jan 23.

PubMed [citation]

PMID:: 24503138

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000654921.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 409 of the ACADVL protein (p.Thr409Met). This variant is present in population databases (rs113994169, gnomAD 0.04%). This missense change has been observed, in combination with a different pathogenic ACADVL variant, in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) (PMID: 24503138, 31031081; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Maori and Pacific ancestry (PMID: 26743058). Homozygous individuals have been reported with abnormal newborn screening lab results but without early-onset or severe symptoms typical for classic VLCAD; however, long term follow-up data is not available to assess risk for late-onset VLCAD (PMID: 24503138). ClinVar contains an entry for this variant (Variation ID: 21013). 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 ACADVL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883345.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ACADVL c.1226C>T; p.Thr409Met variant (rs113994169) has been reported at a high frequency in unaffected individuals of Maori and Pacific ancestry (Ryder 2016). Homozygosity for this variant has been associated with elevated C14:1 acylcarnitine levels during newborn screening, but has not been associated with the development of classical very long-chain acyl CoA dehydrogenase (VLCAD) deficiency (Evans 2016, Merritt 2014, Ryder 2016). However, these studies did not evaluate the occurrence of late-onset VLCAD symptoms during adolescence or adulthood. This variant has more recently been reported to be compound heterozygous with other ACADVL variants in individuals with VLCAD deficiency (Rovelli 2019). The p.Thr409Met variant is reported in ClinVar (Variation ID: 21013). It is observed in the general population with an overall allele frequency of 0.005% (14/282856 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.333). Based on the available information, the clinical significance of this variant is uncertain at this time. References: Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. PMID: 27246109. Merritt JL et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014 Apr;111(4):484-92. PMID: 24503138. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. Ryder B et al. The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment. J Inherit Metab Dis. 2016 May;39(3):409-414. PMID: 26743058.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001365207.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The NM_000018.3:c.1226C>T (NP_000009.1:p.Thr409Met) [GRCH38: NC_000017.11:g.7223687C>T] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001459252.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766631.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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 VLCAD deficiency (MIM#201475). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 19 heterozygotes, 0 homozygotes,). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, C-terminal domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Thr409Arg) has been classified as a VUS by a diagnostic laboratory in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been classified as pathogenic and VUS by diagnostic laboratories in ClinVar. Known to be enriched in Polynesian populations, compound heterozygous individuals are likely to manifest mild disease and homozygotes tend to remain asymptomatic (PMID: 26743058, 35267200, 35400565). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Blood spots from individuals carrying this variant (both homozygous and compound heterozygous), consistently display VLCAD deficiency and elevated C14:1-carnitine levels (PMID:31031081, 26743058, 24503138). (SP) 1207 - Parental origin of the variant is unresolved. Subsequent analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003822474.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004214095.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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