NM_015506.3(MMACHC):c.650A>T (p.Glu217Val) AND Cobalamin C disease

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Apr 11, 2023
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:: RCV000555947.6

Allele description [Variation Report for NM_015506.3(MMACHC):c.650A>T (p.Glu217Val)]

NM_015506.3(MMACHC):c.650A>T (p.Glu217Val)

Genes:

LOC129930446:ATAC-STARR-seq lymphoblastoid active region 972 [Gene]
MMACHC:metabolism of cobalamin associated C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_015506.3(MMACHC):c.650A>T (p.Glu217Val)

HGVS:

NC_000001.11:g.45509016A>T
NG_013378.1:g.13833A>T
NM_001330540.2:c.479A>T
NM_015506.3:c.650A>TMANE SELECT
NP_001317469.1:p.Glu160Val
NP_056321.2:p.Glu217Val
NC_000001.10:g.45974688A>T
NM_015506.2:c.650A>T
p.Glu217Val

Protein change:

E160V

Links:

dbSNP: rs199641732

NCBI 1000 Genomes Browser:

rs199641732

Molecular consequence:

NM_001330540.2:c.479A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015506.3:c.650A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cobalamin C disease
Synonyms:: Cobalamin-C methylmalonic acidemia and homocystinuria; Methylmalonic acidemia and homocystinuria cblC type; Methylmalonic aciduria and homocystinuria, Vitamin B12-responsive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010184; MedGen: C1848561; Orphanet: 26; Orphanet: 79282; OMIM: 277400

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Human DNA sequence from clone RP11-426P2 on chromosome 1, complete sequence
Human DNA sequence from clone RP11-426P2 on chromosome 1, complete sequence
gi|18252288|emb|AL442223.13|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000640289	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002089555	Natera, Inc.	no assertion criteria provided	Uncertain significance (Apr 21, 2018)	germline	clinical testing
SCV002786886	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004178220	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 11, 2023)	germline	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	no	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

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, SCV000640289.2

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

Description

This sequence change replaces glutamic acid with valine at codon 217 of the MMACHC protein (p.Glu217Val). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs199641732, ExAC 0.02%). This missense change has been observed in individual(s) with MMACHC-related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

#	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., SCV002089555.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002786886.1

#	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

From Genome-Nilou Lab, SCV004178220.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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