VCV000496435.11 - ClinVar

NM_015506.3(MMACHC):c.641G>A (p.Arg214His)

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.

(7)

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.

Uncertain significance

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.641G>A (p.Arg214His)

Variation ID: 496435 Accession: VCV000496435.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45509007 (GRCh38) [ NCBI UCSC ] 1: 45974679 (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	Mar 17, 2018	Dec 24, 2023	Apr 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015506.3:c.641G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056321.2:p.Arg214His	missense
NM_001330540.2:c.470G>A	NP_001317469.1:p.Arg157His	missense
NC_000001.11:g.45509007G>A
NC_000001.10:g.45974679G>A
NG_013378.1:g.13824G>A

... more HGVS ... less HGVS

Protein change

R214H, R157H

Other names

Canonical SPDI

NC_000001.11:45509006:G:A

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.

The Genome Aggregation Database (gnomAD) 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00013

Exome Aggregation Consortium (ExAC) 0.00014

The Genome Aggregation Database (gnomAD), exomes 0.00016

Links

ClinGen: CA827818 dbSNP: rs202189863 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.
LOC129930446	-	-	-	GRCh38	-	67
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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 25, 2016	RCV000588709.1
Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001101238.4
Cobalamin C disease	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV001277246.8

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 (Jan 25, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699403.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (1) PubMed: 25668207 Comment: Variant summary: The c.641G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 3/4 in-silico tools predict this variant to … (more) Variant summary: The c.641G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. This variant is found in 17/120988 control chromosomes at a frequency of 0.0001405, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0030542). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Disorders of Intracellular Cobalamin Metabolism Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001257832.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jul 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002776963.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jun 17, 2022)	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: SCV003517951.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the MMACHC protein (p.Arg214His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the MMACHC protein (p.Arg214His). This variant is present in population databases (rs202189863, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 496435). 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: "Deleterious"; PolyPhen-2: "Benign"; 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. (less)
Uncertain significance (Oct 19, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003799487.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: The MMACHC c.641G>A; p.Arg214His variant (rs202189863), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 496435). This … (more) The MMACHC c.641G>A; p.Arg214His variant (rs202189863), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 496435). This variant is found in the general population with an overall allele frequency of 0.016% (44/280864 alleles) in the Genome Aggregation Database. The arginine at codon 214 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.460). Due to limited information, the clinical significance of this variant is uncertain at this time. (less)
Uncertain significance (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: SCV004178217.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (Mar 26, 2018)	no assertion criteria provided Method: clinical testing	Methylmalonic aciduria and homocystinuria cblC type Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001464153.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

Variant summary: The c.641G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. This variant is found in 17/120988 control chromosomes at a frequency of 0.0001405, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0030542). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the MMACHC protein (p.Arg214His). This variant is present in population databases (rs202189863, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 496435). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.

Comment:

The MMACHC c.641G>A; p.Arg214His variant (rs202189863), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 496435). This variant is found in the general population with an overall allele frequency of 0.016% (44/280864 alleles) in the Genome Aggregation Database. The arginine at codon 214 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.460). Due to limited information, the clinical significance of this variant is uncertain at this time.

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
Genetic investigation of bisphosphonate-related osteonecrosis of jaw (BRONJ) via whole exome sequencing and bioinformatics.	Kim JH	PloS one	2015	PMID: 25668207

Text-mined citations for rs202189863 ...

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.641G>A (p.Arg214His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202189863 ...