NM_015506.3(MMACHC):c.347T>C (p.Leu116Pro) AND Cobalamin C disease

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 30, 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:: RCV000001487.15

Allele description [Variation Report for NM_015506.3(MMACHC):c.347T>C (p.Leu116Pro)]

NM_015506.3(MMACHC):c.347T>C (p.Leu116Pro)

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.347T>C (p.Leu116Pro)

HGVS:

NC_000001.11:g.45508282T>C
NG_013378.1:g.13099T>C
NM_001330540.2:c.176T>C
NM_015506.3:c.347T>CMANE SELECT
NP_001317469.1:p.Leu59Pro
NP_056321.2:p.Leu116Pro
NC_000001.10:g.45973954T>C
NM_015506.2:c.347T>C
Q9Y4U1:p.Leu116Pro

Protein change:

L116P; LEU116PRO

Links:

UniProtKB: Q9Y4U1#VAR_024771; OMIM: 609831.0002; dbSNP: rs121918240

NCBI 1000 Genomes Browser:

rs121918240

Molecular consequence:

NM_001330540.2:c.176T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_015506.3:c.347T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021642	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000789773	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 17, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16311595, 19370762, 20631720, 20924684, 22642810 Citation Link,
SCV001162900	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423146	Neurology Department, Peking University First Hospital	no assertion criteria provided	Pathogenic (Apr 23, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002247290	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14568819, 16311595, 18245139, 20631720, 20924684, 28492532
SCV002811453	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 23, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004178158	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
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

Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.

Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B.

Hum Mutat. 2009 Jul;30(7):1072-81. doi: 10.1002/humu.21001.

PubMed [citation]

PMID:: 19370762

Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function.

Froese DS, Krojer T, Wu X, Shrestha R, Kiyani W, von Delft F, Gravel RA, Oppermann U, Yue WW.

Biochemistry. 2012 Jun 26;51(25):5083-90. doi: 10.1021/bi300150y. Epub 2012 Jun 14.

PubMed [citation]

PMID:: 22642810

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000021642.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 patients in whom the diagnosis of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was made after the age of 20 years, Lerner-Ellis et al. (2006) found compound heterozygosity in the MMACHC gene for the most common mutation, 271dupA (609831.0001), which in homozygous state causes early-onset disease, and a 347T-C transition, which was predicted to result in a leu116-to-pro (L116P) substitution.

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

From Counsyl, SCV000789773.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 Baylor Genetics, SCV001162900.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neurology Department, Peking University First Hospital, SCV001423146.1

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

#	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 Invitae, SCV002247290.3

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the MMACHC protein (p.Leu116Pro). This variant is present in population databases (rs121918240, gnomAD 0.04%). This missense change has been observed in individual(s) with homocystinuria, cblC type (PMID: 14568819, 16311595, 18245139, 20631720, 20924684; Invitae). ClinVar contains an entry for this variant (Variation ID: 1422). 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 MMACHC 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

From Fulgent Genetics, Fulgent Genetics, SCV002811453.1

#	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, SCV004178158.1

#	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: Feb 20, 2024

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