VCV000908837.10 - ClinVar

NM_000255.4(MMUT):c.1091A>C (p.Tyr364Ser)

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.

(8)

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
Uncertain significance(5); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000255.4(MMUT):c.1091A>C (p.Tyr364Ser)

Variation ID: 908837 Accession: VCV000908837.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.3 6: 49451707 (GRCh38) [ NCBI UCSC ] 6: 49419420 (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	May 31, 2020	Aug 18, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000255.4:c.1091A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000246.2:p.Tyr364Ser	missense
NC_000006.12:g.49451707T>G
NC_000006.11:g.49419420T>G
NG_007100.1:g.16433A>C

Protein change

Y364S

Other names

Canonical SPDI

NC_000006.12:49451706:T:G

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) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Exome Aggregation Consortium (ExAC) 0.00007

Links

dbSNP: rs563776413 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.
MMUT		-	-	GRCh38 GRCh37	1080	1093

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 due to methylmalonyl-CoA mutase deficiency	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Mar 26, 2024	RCV001159540.8
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jul 6, 2022	RCV001729805.4

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.
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001321258.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Oct 29, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520463.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (2) PubMed: 17823972‚ 27884173 Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following … (more) This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 17823972, 27884173] (less)
Uncertain significance (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002789709.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jul 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003263519.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 17823972‚ 26615597 Comment: This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 364 of the MUT protein (p.Tyr364Ser). … (more) This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 364 of the MUT protein (p.Tyr364Ser). This variant is present in population databases (rs563776413, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of methylmalonic acidemia (PMID: 17823972, 26615597). ClinVar contains an entry for this variant (Variation ID: 908837). 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: "Possibly Damaging"; 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)
Likely benign (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806773.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005189034.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001978599.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980524.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 364 of the MUT protein (p.Tyr364Ser). This variant is present in population databases (rs563776413, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of methylmalonic acidemia (PMID: 17823972, 26615597). ClinVar contains an entry for this variant (Variation ID: 908837). 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: "Possibly Damaging"; 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.

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
Revisiting the morbid genome of Mendelian disorders.	Abouelhoda M	Genome biology	2016	PMID: 27884173
Spectrum of Mutations in 60 Saudi Patients with Mut Methylmalonic Acidemia.	Imtiaz F	JIMD reports	2016	PMID: 26615597
Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE).	Gradinger AB	Human mutation	2007	PMID: 17823972

Text-mined citations for rs563776413 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000255.4(MMUT):c.1091A>C (p.Tyr364Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs563776413 ...