NM_020166.5(MCCC1):c.1303G>A (p.Ala435Thr) AND 3-methylcrotonyl-CoA carboxylase 1 deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000804238.10

Allele description [Variation Report for NM_020166.5(MCCC1):c.1303G>A (p.Ala435Thr)]

NM_020166.5(MCCC1):c.1303G>A (p.Ala435Thr)

Gene:

MCCC1:methylcrotonyl-CoA carboxylase subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q27.1

Genomic location:

Preferred name:

NM_020166.5(MCCC1):c.1303G>A (p.Ala435Thr)

HGVS:

NC_000003.12:g.183039100C>T
NG_008100.1:g.65478G>A
NM_001293273.2:c.952G>A
NM_001363880.1:c.976G>A
NM_020166.5:c.1303G>AMANE SELECT
NP_001280202.1:p.Ala318Thr
NP_001350809.1:p.Ala326Thr
NP_064551.3:p.Ala435Thr
NC_000003.11:g.182756888C>T
NR_120639.2:n.1126G>A
NR_120640.2:n.1970G>A
NM_020166.5:c.1303G>A

Protein change:

A318T

Links:

dbSNP: rs142507365

NCBI 1000 Genomes Browser:

rs142507365

Molecular consequence:

NM_001293273.2:c.952G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363880.1:c.976G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020166.5:c.1303G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_120639.2:n.1126G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_120640.2:n.1970G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: 3-methylcrotonyl-CoA carboxylase 1 deficiency (MCC1D)
Synonyms:: MCCD TYPE 1; METHYLCROTONYLGLYCINURIA TYPE I; MCC 1 deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008861; MedGen: C0268600; Orphanet: 6; OMIM: 210200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000944135	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32746448, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000944135

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 8, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.

Burstein DS, Gaynor JW, Griffis H, Ritter A, Connor MJO, Rossano JW, Lin KY, Ahrens-Nicklas RC.

Pediatr Res. 2021 May;89(6):1470-1476. doi: 10.1038/s41390-020-1101-5. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32746448
PMCID:: PMC8256333

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000944135.7

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 435 of the MCCC1 protein (p.Ala435Thr). This variant is present in population databases (rs142507365, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 32746448; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 649327). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCCC1 protein function. 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

Last Updated: Sep 29, 2024

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