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NM_022132.5(MCCC2):c.1493C>T (p.Ser498Phe) AND 3-methylcrotonyl-CoA carboxylase 2 deficiency

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 6, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV003097750.3

Allele description [Variation Report for NM_022132.5(MCCC2):c.1493C>T (p.Ser498Phe)]

NM_022132.5(MCCC2):c.1493C>T (p.Ser498Phe)

Gene:
MCCC2:methylcrotonyl-CoA carboxylase subunit 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q13.2
Genomic location:
Preferred name:
NM_022132.5(MCCC2):c.1493C>T (p.Ser498Phe)
HGVS:
  • NC_000005.10:g.71652673C>T
  • NG_008882.1:g.70386C>T
  • NM_001363147.1:c.1379C>T
  • NM_022132.5:c.1493C>TMANE SELECT
  • NP_001350076.1:p.Ser460Phe
  • NP_071415.1:p.Ser498Phe
  • NC_000005.9:g.70948500C>T
  • NM_022132.4:c.1493C>T
Protein change:
S460F
Molecular consequence:
  • NM_001363147.1:c.1379C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_022132.5:c.1493C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
3-methylcrotonyl-CoA carboxylase 2 deficiency
Synonyms:
METHYLCROTONYLGLYCINURIA, TYPE II; 3 alpha methylcrotonyl-CoA carboxylase 2 deficiency; 3 alpha methylcrotonylglycinuria 2; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008862; MedGen: C1859499; Orphanet: 6; OMIM: 210210

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003478757Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 6, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003835563Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Sep 21, 2022) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Invitae, SCV003478757.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 498 of the MCCC2 protein (p.Ser498Phe). This variant is present in population databases (rs757286719, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MCCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1708798). 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 MCCC2 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV003835563.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024