NM_000429.3(MAT1A):c.529C>T (p.Arg177Trp) AND Hepatic methionine adenosyltransferase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 11, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000634908.13

Allele description [Variation Report for NM_000429.3(MAT1A):c.529C>T (p.Arg177Trp)]

NM_000429.3(MAT1A):c.529C>T (p.Arg177Trp)

Gene:

MAT1A:methionine adenosyltransferase 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.3

Genomic location:

Preferred name:

NM_000429.3(MAT1A):c.529C>T (p.Arg177Trp)

HGVS:

NC_000010.11:g.80280193G>A
NG_008083.1:g.14486C>T
NM_000429.3:c.529C>TMANE SELECT
NP_000420.1:p.Arg177Trp
NC_000010.10:g.82039949G>A
NM_000429.2:c.529C>T

Protein change:

R177W

Links:

dbSNP: rs376757912

NCBI 1000 Genomes Browser:

rs376757912

Molecular consequence:

NM_000429.3:c.529C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hepatic methionine adenosyltransferase deficiency
Synonyms:: MAT I/III DEFICIENCY; Isolated Persistent Hypermethioninemia; Methionine adenosyltransferase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009607; MeSH: C564683; MedGen: C0268621; Orphanet: 168598; OMIM: 250850

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000756278	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24445979, 26289392, 28186605, 31061746, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000756278

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Thirteen Patients with MAT1A Mutations Detected Through Newborn Screening: 13 Years' Experience.

Chadwick S, Fitzgerald K, Weiss B, Ficicioglu C.

JIMD Rep. 2014;14:71-6. doi: 10.1007/8904_2013_286. Epub 2014 Jan 21.

PubMed [citation]

PMID:: 24445979
PMCID:: PMC4213332

Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes.

Chien YH, Abdenur JE, Baronio F, Bannick AA, Corrales F, Couce M, Donner MG, Ficicioglu C, Freehauf C, Frithiof D, Gotway G, Hirabayashi K, Hofstede F, Hoganson G, Hwu WL, James P, Kim S, Korman SH, Lachmann R, Levy H, Lindner M, Lykopoulou L, et al.

Orphanet J Rare Dis. 2015 Aug 20;10:99. doi: 10.1186/s13023-015-0321-y. Review.

PubMed [citation]

PMID:: 26289392
PMCID:: PMC4545930

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000756278.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 177 of the MAT1A protein (p.Arg177Trp). This variant is present in population databases (rs376757912, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive hypermethioninemia (PMID: 24445979, 26289392, 28186605, 31061746; internal data). 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: 426944). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAT1A protein function. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003808290.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003808290	Revvity Omics, Revvity	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003808290

Revvity Omics, Revvity

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 1, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Mar 16, 2025

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