VCV000004807.6 - ClinVar

NM_017672.6(TRPM7):c.4445C>T (p.Thr1482Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017672.6(TRPM7):c.4445C>T (p.Thr1482Ile)

Variation ID: 4807 Accession: VCV000004807.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.2 15: 50586433 (GRCh38) [ NCBI UCSC ] 15: 50878630 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 11, 2017	Oct 8, 2024	Mar 31, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_017672.6:c.4445C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060142.3:p.Thr1482Ile	missense
NM_001301212.2:c.4445C>T	NP_001288141.1:p.Thr1482Ile	missense
NM_017672.5:c.4445C>T
NR_149152.2:n.4659C>T		non-coding transcript variant
NR_149153.2:n.4582C>T		non-coding transcript variant
NR_149154.2:n.4509C>T		non-coding transcript variant
NC_000015.10:g.50586433G>A
NC_000015.9:g.50878630G>A
NG_021363.2:g.105383C>T
LRG_1192:g.105383C>T
LRG_1192t1:c.4445C>T	LRG_1192p1:p.Thr1482Ile
	Q96QT4:p.Thr1482Ile

... more HGVS ... less HGVS

Protein change

T1482I

Other names

TRPM7, THR1482ILE (rs8042919)

Canonical SPDI

NC_000015.10:50586432:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.07588 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.07152

The Genome Aggregation Database (gnomAD) 0.07196

Trans-Omics for Precision Medicine (TOPMed) 0.07391

1000 Genomes Project 0.07588

The Genome Aggregation Database (gnomAD), exomes 0.08471

Exome Aggregation Consortium (ExAC) 0.08703

Links

ClinGen: CA117098 UniProtKB: Q96QT4#VAR_019967 OMIM: 605692.0001 dbSNP: rs8042919 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TRPM7		-	-	GRCh38 GRCh37	137	190

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1, susceptibility to	risk factor (1)	no assertion criteria provided	Jan 5, 2010	RCV000005076.4
Juvenile amyotrophic lateral sclerosis	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2020	RCV001095429.1
not provided	Benign (1)	criteria provided, single submitter	Nov 12, 2018	RCV001723538.2
TRPM7-related disorder	Benign (1)	no assertion criteria provided	Aug 26, 2024	RCV003964793.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Juvenile amyotrophic lateral sclerosis Affected status: yes Allele origin: germline	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University Accession: SCV001251011.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Number of individuals with the variant: 2 Geographic origin: Anatolian Peninsula
Benign (Nov 12, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001950700.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 16051700, 25681989, 29874175, 32579787)
risk factor (Jan 05, 2010)	no assertion criteria provided Method: literature only	AMYOTROPHIC LATERAL SCLEROSIS-PARKINSONISM/DEMENTIA COMPLEX 1, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025252.3 First in ClinVar: Apr 04, 2013 Last updated: May 11, 2017	Publications: PubMed (2) PubMed: 16051700‚ 19405049 Comment on evidence: Hermosura et al. (2005) reported a heterozygous C-to-T transition in the TRPM7 gene, resulting in a thr1482-to-ile (T1482I; rs8042919) substitution, in 5 of 22 patients … (more) Hermosura et al. (2005) reported a heterozygous C-to-T transition in the TRPM7 gene, resulting in a thr1482-to-ile (T1482I; rs8042919) substitution, in 5 of 22 patients with ALS-Parkinsonism/dementia complex of Guam (105500). The T1482I variant was not identified in 23 control Chamorro individuals. Threonine-1482 is a highly conserved residue that lies between the channel and kinase domains of the protein and is predicted to be a potential substrate for autophosphorylation. In vitro functional expression studies showed that mutant channels were functional but showed increased susceptibility to inhibition by intracellular magnesium concentrations compared to wildtype channels. Noting that the neurodegenerative disorders on Guam had been related to an environment deficient in calcium and magnesium, Hermosura et al. (2005) suggested that the T1482I variant in the TRPM7 gene may confer susceptibility to disease development. Hara et al. (2010) did not find an association between the TRPM7 T1482I variant and disease in affected members from a large extended family with ALS-PDC from the Kii peninsula of Japan. The frequency of the T1482I variant in the family was similar to that observed in controls. (less)
Benign (Aug 26, 2024)	no assertion criteria provided Method: clinical testing	TRPM7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004793239.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
TRPM7 is not associated with amyotrophic lateral sclerosis-parkinsonism dementia complex in the Kii peninsula of Japan.	Hara K	American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics	2010	PMID: 19405049
A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders.	Hermosura MC	Proceedings of the National Academy of Sciences of the United States of America	2005	PMID: 16051700

Text-mined citations for rs8042919 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_017672.6(TRPM7):c.4445C>T (p.Thr1482Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs8042919 ...