NM_020166.5(MCCC1):c.196C>T (p.Arg66Cys) AND 3 Methylcrotonyl-CoA carboxylase 1 deficiency

Clinical significance:Likely pathogenic (Last evaluated: Aug 17, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000653493.2

Allele description [Variation Report for NM_020166.5(MCCC1):c.196C>T (p.Arg66Cys)]

NM_020166.5(MCCC1):c.196C>T (p.Arg66Cys)

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.196C>T (p.Arg66Cys)
HGVS:
  • NC_000003.12:g.183092486G>A
  • NG_008100.1:g.12092C>T
  • NM_001293273.2:c.44+2073C>T
  • NM_001363880.1:c.-55+2073C>T
  • NM_020166.5:c.196C>TMANE SELECT
  • NP_064551.3:p.Arg66Cys
  • NC_000003.11:g.182810274G>A
  • NM_020166.4:c.196C>T
  • NR_120640.2:n.863C>T
Protein change:
R66C
Links:
dbSNP: rs754460336
NCBI 1000 Genomes Browser:
rs754460336
Molecular consequence:
  • NM_001293273.2:c.44+2073C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001363880.1:c.-55+2073C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_020166.5:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_120640.2:n.863C>T - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000775373Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 17, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot 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

Details of each submission

From Invitae, SCV000775373.2

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

Description

This sequence change replaces arginine with cysteine at codon 66 of the MCCC1 protein (p.Arg66Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs754460336, ExAC 0.02%). This variant has been observed in combination with other MCCC1 variants in individuals affected with 3-methylcrotonyl-CoA carboxylase deficiency (Invitae). In one of these individuals, the variant occurs with a pathogenic variant (p.Asn560Lysfs*10) in MCCC1 and family studies indicate these two variants are on opposite chromosomes (in trans), which suggests the c.196C>T substitution may contribute to disease. ClinVar contains an entry for this variant (Variation ID: 542949). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 24, 2021

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