VCV000161117.16 - ClinVar

NM_015506.3(MMACHC):c.276G>T (p.Glu92Asp)

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.

(5)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015506.3(MMACHC):c.276G>T (p.Glu92Asp)

Variation ID: 161117 Accession: VCV000161117.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45507550 (GRCh38) [ NCBI UCSC ] 1: 45973222 (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	Jan 15, 2018	Jun 17, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015506.3:c.276G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056321.2:p.Glu92Asp	missense
NM_001330540.2:c.105G>T	NP_001317469.1:p.Glu35Asp	missense
NC_000001.11:g.45507550G>T
NC_000001.10:g.45973222G>T
NG_013378.1:g.12367G>T

... more HGVS ... less HGVS

Protein change

E92D, E35D

Other names

Canonical SPDI

NC_000001.11:45507549:G:T

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

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA272838 OMIM: 609831.0008 dbSNP: rs556977618 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	620

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.
Cobalamin C disease	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000148298.18

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.
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162897.2 First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004178145.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001373668.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 20652818‚ 23837176‚ 25894566‚ 17576681‚ 9536098 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 92 of the MMACHC … (more) This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 92 of the MMACHC protein (p.Glu92Asp). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs556977618, gnomAD 0.004%). This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 20652818, 23837176, 25894566). ClinVar contains an entry for this variant (Variation ID: 161117). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 01, 2013)	no assertion criteria provided Method: literature only	METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000195686.2 First in ClinVar: Dec 07, 2014 Last updated: Jan 15, 2018	Publications: PubMed (1) PubMed: 23837176 Comment on evidence: In 3 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency (MAHCC; 277400), Komhoff et al. (2013) identified compound heterozygosity … (more) In 3 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency (MAHCC; 277400), Komhoff et al. (2013) identified compound heterozygosity for a c.276G-T transversion in the MMACHC gene, resulting in a glu92-to-asp (E92D) substitution. Two patients also carried the common 271dupA (609831.0001) mutation on the other allele; the third patient was compound heterozygous for a different frameshift mutation. The patients were of Spanish/Turkish or Dutch ethnicity. Because another patient with a synonymous change at that position was identified (see 609831.0009), the authors concluded that the actual effect of the mutation, which affects the last nucleotide of exon 2, is aberrant splicing and ultimately deletion of the erroneous pre-mRNA via nonsense-mediated decay. (less)
Pathogenic (Sep 17, 2020)	no assertion criteria provided Method: clinical testing	Methylmalonic aciduria and homocystinuria cblC type Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089529.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 92 of the MMACHC protein (p.Glu92Asp). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs556977618, gnomAD 0.004%). This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 20652818, 23837176, 25894566). ClinVar contains an entry for this variant (Variation ID: 161117). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Nephrotic syndrome and thrombotic microangiopathy caused by cobalamin C deficiency.	Koenig JC	Pediatric nephrology (Berlin, Germany)	2015	PMID: 25894566
Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.	Kömhoff M	Pediatrics	2013	PMID: 23837176
CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency.	Bouts AH	Pediatric nephrology (Berlin, Germany)	2010	PMID: 20652818
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs556977618 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_015506.3(MMACHC):c.276G>T (p.Glu92Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs556977618 ...