NM_000481.4(AMT):c.173C>T (p.Pro58Leu) AND Non-ketotic hyperglycinemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 12, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001248283.5

Allele description [Variation Report for NM_000481.4(AMT):c.173C>T (p.Pro58Leu)]

NM_000481.4(AMT):c.173C>T (p.Pro58Leu)

Gene:

AMT:aminomethyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_000481.4(AMT):c.173C>T (p.Pro58Leu)

HGVS:

NC_000003.12:g.49422189G>A
NG_015986.1:g.5490C>T
NG_033046.1:g.12136C>T
NM_000481.4:c.173C>TMANE SELECT
NM_001164710.2:c.173C>T
NM_001164711.2:c.90+172C>T
NM_001164712.2:c.173C>T
NP_000472.2:p.Pro58Leu
NP_001158182.1:p.Pro58Leu
NP_001158184.1:p.Pro58Leu
LRG_537t1:c.173C>T
LRG_537:g.5490C>T
NC_000003.11:g.49459622G>A
NC_000003.11:g.49459622G>A
NM_000481.3:c.173C>T
NR_028435.2:n.182C>T

Protein change:

P58L

Links:

dbSNP: rs1008341193

NCBI 1000 Genomes Browser:

rs1008341193

Molecular consequence:

NM_001164711.2:c.90+172C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000481.4:c.173C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164710.2:c.173C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164712.2:c.173C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_028435.2:n.182C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Non-ketotic hyperglycinemia
Synonyms:: Glycine encephalopathy; Nonketotic hyperglycinemia
Identifiers:: MONDO: MONDO:0011612; MedGen: C0751748; Orphanet: 407; OMIM: PS605899; Human Phenotype Ontology: HP:0008288

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001421756	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 12, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001467334	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 13, 2020)	germline	clinical testing
SCV003807716	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 5, 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

SCV001421756

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 12, 2022)

germline

clinical testing

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

SCV001467334

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Aug 13, 2020)

germline

clinical testing

SCV003807716

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 5, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001421756.2

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the AMT protein (p.Pro58Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with AMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 972290). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AMT protein function. 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.

#	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 Natera, Inc., SCV001467334.1

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

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807716.1

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

Description

ACMG classification criteria: PM2 moderated, PP3 supporting, PP4

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

Last Updated: Sep 29, 2024

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