NM_000156.6(GAMT):c.481A>T (p.Lys161Ter) AND Cerebral creatine deficiency syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 9, 2023
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:: RCV001389010.10

Allele description [Variation Report for NM_000156.6(GAMT):c.481A>T (p.Lys161Ter)]

NM_000156.6(GAMT):c.481A>T (p.Lys161Ter)

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.481A>T (p.Lys161Ter)

Other names:

NM_000156.6(GAMT):c.481A>T; p.Lys161Ter

HGVS:

NC_000019.10:g.1399005T>A
NG_009785.1:g.7549A>T
NM_000156.6:c.481A>TMANE SELECT
NM_138924.3:c.481A>T
NP_000147.1:p.Lys161Ter
NP_620279.1:p.Lys161Ter
NC_000019.9:g.1399004T>A
NM_000156.4:c.481A>T

Protein change:

K161*

Links:

dbSNP: rs1057524499

NCBI 1000 Genomes Browser:

rs1057524499

Molecular consequence:

NM_000156.6:c.481A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_138924.3:c.481A>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001590214	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15108290, 28492532
SCV001999916	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 13, 2022)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001590214

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 9, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001999916

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 13, 2022)

germline

curation

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Characterization of seven novel mutations in seven patients with GAMT deficiency.

Item CB, Mercimek-Mahmutoglu S, Battini R, Edlinger-Horvat C, Stromberger C, Bodamer O, Mühl A, Vilaseca MA, Korall H, Stöckler-Ipsiroglu S.

Hum Mutat. 2004 May;23(5):524.

PubMed [citation]

PMID:: 15108290

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590214.4

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

Description

This sequence change creates a premature translational stop signal (p.Lys161*) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). 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 GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 392462). 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001999916.3

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

Description

The p.Lys161Ter variant in GAMT has not been previously reported in individuals with cerebral creatine deficiency syndrome but has been identified in 0.002% (2/128668) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1057524499). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 392462) and has been interpreted as likely pathogenic by GeneDx and pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 161, which is predicted to lead to a truncated or absent protein. Loss of function of the GAMT gene is an established disease mechanism in cerebral creatine deficiency syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM2_supporting, PVS1 (Richards 2015).

#	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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