VCV000203833.15 - ClinVar

NM_015506.3(MMACHC):c.382TAC[2] (p.Tyr130del)

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.

(9)

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/Likely 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.382TAC[2] (p.Tyr130del)

Variation ID: 203833 Accession: VCV000203833.15

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 1p34.1 1: 45508317-45508319 (GRCh38) [ NCBI UCSC ] 1: 45973989-45973991 (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	Jul 18, 2015	Jun 17, 2024	Mar 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015506.3:c.382TAC[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056321.2:p.Tyr130del	inframe deletion
NM_015506.3:c.388_390del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_015506.3:c.388_390delTAC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001330540.2:c.211TAC[2]	NP_001317469.1:p.Tyr73del	inframe deletion
NM_015506.2:c.388_390del
NC_000001.11:g.45508317TAC[2]
NC_000001.10:g.45973989TAC[2]
NG_013378.1:g.13134TAC[2]

... more HGVS ... less HGVS

Protein change

Y130del, Y73del

Other names

Canonical SPDI

NC_000001.11:45508316:TACTACTAC:TACTAC

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.

Links

ClinGen: CA312739 dbSNP: rs796051998 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.
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 23, 2014	RCV000186033.1
Cobalamin C disease	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 4, 2024	RCV000641155.17
MMACHC-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 18, 2022	RCV003407684.4

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 (Oct 23, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238997.2 First in ClinVar: Jul 18, 2015 Last updated: Jul 18, 2015	Comment: The c.388_390delTAC mutation has been reported previously in association with cblC deficiency (Lerner-Ellis, et al., 2006). This mutation causes the deletion of a Tyrosine codon … (more) The c.388_390delTAC mutation has been reported previously in association with cblC deficiency (Lerner-Ellis, et al., 2006). This mutation causes the deletion of a Tyrosine codon at amino acid position 130, denoted p.Tyr130del. The variant is found in MMA-MET panel(s). (less)
Likely pathogenic (Dec 23, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002051351.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Publications: PubMed (3) PubMed: 16311595‚ 33473346‚ 24126030 Comment: Variant summary: MMACHC c.388_390delTAC (p.Tyr130del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more) Variant summary: MMACHC c.388_390delTAC (p.Tyr130del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249426 control chromosomes. c.388_390delTAC has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with cobalamin C type Methylmalonic Acidemia With Homocystinuria (example, Bourque_2021, Lerner-Ellis_2006, Gizicki_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Apr 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809815.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: yes Allele origin: biparental	Daryl Scott Lab, Baylor College of Medicine Accession: SCV004102686.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Aug 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MMACHC-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114095.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MMACHC c.388_390delTAC variant is predicted to result in an in-frame deletion (p.Tyr130del). This variant is a recurrent variant that has been reported in the … (more) The MMACHC c.388_390delTAC variant is predicted to result in an in-frame deletion (p.Tyr130del). This variant is a recurrent variant that has been reported in the homozygous state or along with a second pathogenic MMACHC variant in multiple individuals with confirmed methylmalonic aciduria, cblC type (Lerner-Ellis et al. 2006. PubMed ID: 16311595; Gizicki et al. 2013. PubMed ID: 24126030; Bourque et al. 2020. PubMed ID: 33473346). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45973988-TTAC-T). This variant is interpreted as pathogenic. (less)
Likely 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: SCV004178160.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely pathogenic (Sep 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023490.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 25, 2024)	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: SCV000762780.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 16311595‚ 24126030 Comment: This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the MMACHC protein (p.Tyr130del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the MMACHC protein (p.Tyr130del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771707283, gnomAD 0.004%). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria due to cobalamin C deficiency (PMID: 16311595, 24126030; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203833). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162903.2 First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024

Comment:

The c.388_390delTAC mutation has been reported previously in association with cblC deficiency (Lerner-Ellis, et al., 2006). This mutation causes the deletion of a Tyrosine codon at amino acid position 130, denoted p.Tyr130del. The variant is found in MMA-MET panel(s).

Comment:

Variant summary: MMACHC c.388_390delTAC (p.Tyr130del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249426 control chromosomes. c.388_390delTAC has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with cobalamin C type Methylmalonic Acidemia With Homocystinuria (example, Bourque_2021, Lerner-Ellis_2006, Gizicki_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

The MMACHC c.388_390delTAC variant is predicted to result in an in-frame deletion (p.Tyr130del). This variant is a recurrent variant that has been reported in the homozygous state or along with a second pathogenic MMACHC variant in multiple individuals with confirmed methylmalonic aciduria, cblC type (Lerner-Ellis et al. 2006. PubMed ID: 16311595; Gizicki et al. 2013. PubMed ID: 24126030; Bourque et al. 2020. PubMed ID: 33473346). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45973988-TTAC-T). This variant is interpreted as pathogenic.

Comment:

This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the MMACHC protein (p.Tyr130del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771707283, gnomAD 0.004%). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria due to cobalamin C deficiency (PMID: 16311595, 24126030; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203833). 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
Outcomes of patients with cobalamin C deficiency: A single center experience.	Bourque DK	JIMD reports	2020	PMID: 33473346
Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type.	Gizicki R	Ophthalmology	2014	PMID: 24126030
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.	Lerner-Ellis JP	Nature genetics	2006	PMID: 16311595

Text-mined citations for rs796051998 ...

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.382TAC[2] (p.Tyr130del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs796051998 ...