NM_000156.6(GAMT):c.148A>C (p.Met50Leu) AND Cerebral creatine deficiency syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 29, 2021
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:: RCV001851745.4

Allele description [Variation Report for NM_000156.6(GAMT):c.148A>C (p.Met50Leu)]

NM_000156.6(GAMT):c.148A>C (p.Met50Leu)

Genes:

LOC130062945:ATAC-STARR-seq lymphoblastoid silent region 9707 [Gene]
GAMT:guanidinoacetate N-methyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_000156.6(GAMT):c.148A>C (p.Met50Leu)

Other names:

NM_000156.6(GAMT):c.148A>C

HGVS:

NC_000019.10:g.1401329T>G
NG_009785.1:g.5225A>C
NM_000156.6:c.148A>CMANE SELECT
NM_138924.3:c.148A>C
NP_000147.1:p.Met50Leu
NP_620279.1:p.Met50Leu
NC_000019.9:g.1401328T>G
Q14353:p.Met50Leu

Protein change:

M50L; MET50LEU

Links:

UniProtKB: Q14353#VAR_058103; OMIM: 601240.0005; dbSNP: rs104894694

NCBI 1000 Genomes Browser:

rs104894694

Molecular consequence:

NM_000156.6:c.148A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_138924.3:c.148A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cerebral creatine deficiency syndrome (CCAD)
Synonyms:: Creatine deficiency syndromes
Identifiers:: MONDO: MONDO:0000456; MedGen: C5244016; Orphanet: 79172; OMIM: PS300352

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002140605	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 29, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24415674, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002140605

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 29, 2021)

germline

clinical testing

PubMed (2)
[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 new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene.

Mercimek-Mahmutoglu S, Ndika J, Kanhai W, de Villemeur TB, Cheillan D, Christensen E, Dorison N, Hannig V, Hendriks Y, Hofstede FC, Lion-Francois L, Lund AM, Mundy H, Pitelet G, Raspall-Chaure M, Scott-Schwoerer JA, Szakszon K, Valayannopoulos V, Williams M, Salomons GS.

Hum Mutat. 2014 Apr;35(4):462-9. doi: 10.1002/humu.22511. Epub 2014 Mar 6.

PubMed [citation]

PMID:: 24415674

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002140605.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 50 of the GAMT protein (p.Met50Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This missense change has been observed in individual(s) with GAMT deficiency (PMID: 24415674). 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. Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). 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"). ClinVar contains an entry for this variant (Variation ID: 8305).

#	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

Last Updated: Sep 29, 2024

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