NM_001482.3(GATM):c.965G>C (p.Arg322Pro) AND Fanconi renotubular syndrome 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 24, 2022
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV002279784.1

Allele description [Variation Report for NM_001482.3(GATM):c.965G>C (p.Arg322Pro)]

NM_001482.3(GATM):c.965G>C (p.Arg322Pro)

Gene:

GATM:glycine amidinotransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_001482.3(GATM):c.965G>C (p.Arg322Pro)

HGVS:

NC_000015.10:g.45366059C>G
NG_011674.2:g.41259G>C
NM_001321015.2:c.578G>C
NM_001482.3:c.965G>CMANE SELECT
NP_001307944.1:p.Arg193Pro
NP_001473.1:p.Arg322Pro
NC_000015.9:g.45658257C>G

Protein change:

R193P

Links:

dbSNP: rs1325460408

NCBI 1000 Genomes Browser:

rs1325460408

Molecular consequence:

NM_001321015.2:c.578G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001482.3:c.965G>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

dominant_negative_variant [Sequence Ontology: SO:0002052]

Observations:

Condition(s)

Name:: Fanconi renotubular syndrome 1
Synonyms:: FRTS1; Toni-Debre-Fanconi syndrome; Neonatal De Toni-Debre-Fanconi syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0024525; MedGen: C4551503; OMIM: 134600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002567815	Translational Genomics Group, Broad institute of MIT and Harvard	no assertion criteria provided	Likely pathogenic (Aug 24, 2022)	maternal	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

SCV002567815

Translational Genomics Group, Broad institute of MIT and Harvard

no assertion criteria provided

Likely pathogenic
(Aug 24, 2022)

maternal

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	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.

Reichold M, Klootwijk ED, Reinders J, Otto EA, Milani M, Broeker C, Laing C, Wiesner J, Devi S, Zhou W, Schmitt R, Tegtmeier I, Sterner C, Doellerer H, Renner K, Oefner PJ, Dettmer K, Simbuerger JM, Witzgall R, Stanescu HC, Dumitriu S, Iancu D, et al.

J Am Soc Nephrol. 2018 Jul;29(7):1849-1858. doi: 10.1681/ASN.2017111179. Epub 2018 Apr 13.

PubMed [citation]

PMID:: 29654216
PMCID:: PMC6050927

Details of each submission

From Translational Genomics Group, Broad institute of MIT and Harvard, SCV002567815.1

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

Description

Variant confirmed by Sanger sequencing and also present in affected mother

Description

Four heterozygous variants in GATM, p.(Pro320Ser), p.(Thr336Ala), p.(Thre336Ile) and p.(Pro341Leu), have previously been described as pathogenic for renal Fanconi syndrome with progression to kidney failure (Reichold et al JASN). All 4 variants were fully penetrant and clustered on conserved proline and threonine residues representing <5% of the protein. We identified a novel variant in GATM p.(Arg322Pro), segregating in an affected mother-daughter pair with idiopathic RFS. This variant is two amino acids downstream of a previously described pathogenic variant, p.(Pro320Ser). We perfomed molecular dynamics simulations which support pathogenicity of our novel variant through a consistent dynamic signature to pathogenic variants identified by Reichold et al.

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

Last Updated: Dec 24, 2023

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