VCV000495216.6 - ClinVar

NM_015506.3(MMACHC):c.158T>C (p.Leu53Pro)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015506.3(MMACHC):c.158T>C (p.Leu53Pro)

Variation ID: 495216 Accession: VCV000495216.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45507432 (GRCh38) [ NCBI UCSC ] 1: 45973104 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 30, 2018	Jun 9, 2024	Dec 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015506.3:c.158T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056321.2:p.Leu53Pro	missense
NM_001330540.2:c.-14T>C		5 prime UTR
NC_000001.11:g.45507432T>C
NC_000001.10:g.45973104T>C
NG_013378.1:g.12249T>C

... more HGVS ... less HGVS

Protein change

L53P

Other names

Canonical SPDI

NC_000001.11:45507431:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Decreased function

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA827654 OMIM: 609831.0013 dbSNP: rs756980496 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MMACHC		-	-	GRCh38 GRCh37	527	619

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC	Pathogenic (1)	no assertion criteria provided	Nov 19, 2021	RCV000585794.6
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 11, 2023	RCV003323623.2
Cobalamin C disease	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 20, 2023	RCV003465319.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jul 11, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029140.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (2) PubMed: 24126030‚ 29302025 Comment: Variant summary: MMACHC c.158T>C (p.Leu53Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: MMACHC c.158T>C (p.Leu53Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249504 control chromosomes (gnomAD). c.158T>C has been reported in the literature as a compound heterozygous genotype together with a pathogenic variant in an asymptomatic individual with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) who also had an affected sibling who was not genetically tested (Gizicki_2014). It has also been reported in a case of compound epigenetic-genetic heterozygosity, where the affected individual was heterozygous for c.158T>C in MMACHC and also harbored a variant in the PRDX1 gene on the opposite chromosome (i.e. in trans) which resulted in the epigenetic silencing of the second MMACHC allele (Gueant_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24126030, 29302025). No clinical diagnostic laboratories have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further clinical and/or functional evidence becomes available. (less)
Likely pathogenic (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193213.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Dec 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing, in vitro	Cobalamin C disease (Autosomal recessive inheritance) Affected status: not applicable, yes Allele origin: germline, not applicable	Centre de Genetique Humaine, Institut de Pathologie et de Genetique Accession: SCV004697463.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024	Publications: PubMed (1) PubMed: 38387306 Comment: Patients (n=3) are compound heterozygotes for this allele and the severe and common NM_015506.3:c.271dupA p.(Arg91Lysfs14). Patient 1 and 3 were picked up by urine NBS … (more) Patients (n=3) are compound heterozygotes for this allele and the severe and common NM_015506.3:c.271dupA p.(Arg91Lysfs14). Patient 1 and 3 were picked up by urine NBS (in Québec), patient 2 was the older asymptomatic 4 y.o. sister of patient 1. Biochemical evaluation highlighted : elevated plasma MMA, elevated urine MMA, elevated total plasma homocysteine and low/normal methionine. Skin fibroblasts from patient 1 & 3 showed decreased propionate and methylTHF incorporation that was partially rescued by hydroxycobalamin addition to the culture medium (Rosenblatt's lab). (less) Observation 1: Clinical Features: Methylmalonic aciduria (present) Age: 0-9 years Sex: female Comment on evidence: Compound heterozygosity with : c.271dupA PMID: 38387306 Observation 2: Clinical Features: Methylmalonic aciduria (present) Age: 0-9 years Sex: male Comment on evidence: Compound heterozygosity with : c.271dupA PMID: 38387306 Observation 3: Clinical Features: Methylmalonic aciduria (present) Age: 0-9 years Sex: female Ethnicity/Population group: French-Canadian Geographic origin: Québec Comment on evidence: Compound heterozygosity with c.271dupA PMID: 38387306 Observation 4: Sex: mixed Method: The in vitro studies are based on incorporation of label from [14C]propionate and 5-[14C]methyltetrahydrofolate into cellular macromolecules (measuring function of methylmalonylCoA mutase and methionine synthase, respectively) and decreased synthesis of both AdoCbl and MeCbl from exogenous [57Co]-labeled CNCbl. These analysis have been performed in Rosenblatt's lab by a team that has more than 40 years of experience in cobalamin metabolism. More details can be found here : PMID: 38387306 Result: Skin fibroblasts from patient 1 & 3 showed decreased propionate and methylTHF incorporation that was partially rescued by hydroxycobalamin addition to the culture medium. Cobalamin species in skin fibroblasts were qualitatively different than from healthy controls.
Pathogenic (Nov 19, 2021)	no assertion criteria provided Method: literature only	METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000693728.3 First in ClinVar: Mar 14, 2018 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 29302025 Comment on evidence: In a 59-year-old Caucasian man (WG-4152) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC … (more) In a 59-year-old Caucasian man (WG-4152) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a c.158T-C transition, resulting in a leu53-to-pro (L53P) substitution, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0001). (less)

Comment:

Variant summary: MMACHC c.158T>C (p.Leu53Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249504 control chromosomes (gnomAD). c.158T>C has been reported in the literature as a compound heterozygous genotype together with a pathogenic variant in an asymptomatic individual with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) who also had an affected sibling who was not genetically tested (Gizicki_2014). It has also been reported in a case of compound epigenetic-genetic heterozygosity, where the affected individual was heterozygous for c.158T>C in MMACHC and also harbored a variant in the PRDX1 gene on the opposite chromosome (i.e. in trans) which resulted in the epigenetic silencing of the second MMACHC allele (Gueant_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24126030, 29302025). No clinical diagnostic laboratories have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further clinical and/or functional evidence becomes available.

Comment:

Patients (n=3) are compound heterozygotes for this allele and the severe and common NM_015506.3:c.271dupA p.(Arg91Lysfs*14). Patient 1 and 3 were picked up by urine NBS (in Québec), patient 2 was the older asymptomatic 4 y.o. sister of patient 1. Biochemical evaluation highlighted : elevated plasma MMA, elevated urine MMA, elevated total plasma homocysteine and low/normal methionine. Skin fibroblasts from patient 1 & 3 showed decreased propionate and methylTHF incorporation that was partially rescued by hydroxycobalamin addition to the culture medium (Rosenblatt's lab).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Decreased function	The in vitro studies are based on incorporation of label from [14C]propionate and 5-[14C]methyltetrahydrofolate into cellular macromolecules (measuring function of methylmalonylCoA mutase and methionine synthase, respectively) and decreased synthesis of both AdoCbl and MeCbl from exogenous [57Co]-labeled CNCbl. These analysis have been performed in Rosenblatt's lab by a team that has more than 40 years of experience in cobalamin metabolism. More details can be found here : PMID: 38387306	Skin fibroblasts from patient 1 & 3 showed decreased propionate and methylTHF incorporation that was partially rescued by hydroxycobalamin addition to the culture medium. Cobalamin species in skin fibroblasts were qualitatively different than from healthy controls.	Centre de Genetique Humaine, Institut de Pathologie et de Genetique Accession: SCV004697463.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.	Demaret T	Molecular genetics and metabolism	2024	PMID: 38387306
APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.	Guéant JL	Nature communications	2018	PMID: 29302025
Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type.	Gizicki R	Ophthalmology	2014	PMID: 24126030

Text-mined citations for rs756980496 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_015506.3(MMACHC):c.158T>C (p.Leu53Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs756980496 ...