VCV002574088.2 - ClinVar

NM_017849.4(TMEM127):c.2T>C (p.Met1Thr)

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017849.4(TMEM127):c.2T>C (p.Met1Thr)

Variation ID: 2574088 Accession: VCV002574088.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q11.2 2: 96265380 (GRCh38) [ NCBI UCSC ] 2: 96931118 (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	Feb 4, 2024	May 1, 2024	Oct 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_017849.4:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060319.1:p.Met1Thr	missense initiator codon variant
NM_001193304.3:c.2T>C	NP_001180233.1:p.Met1Thr	missense initiator codon variant
NM_001407283.1:c.-9+489T>C		intron variant
NC_000002.12:g.96265380A>G
NC_000002.11:g.96931118A>G
NG_027695.1:g.5634T>C
NG_167351.1:g.224A>G
LRG_528:g.5634T>C
LRG_528t1:c.2T>C	LRG_528p1:p.Met1Thr

... more HGVS ... less HGVS

Protein change

M1T

Other names

Canonical SPDI

NC_000002.12:96265379:A:G

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.

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

Links

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.
TMEM127		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	776	1022
LOC129934333	-	-	-	GRCh38	-	200

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.
Pheochromocytoma	Likely pathogenic (1)	no assertion criteria provided	Jul 21, 2023	RCV003485907.1
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 6, 2023	RCV004333281.1

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.
Pathogenic (Oct 06, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005027510.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the TMEM127 gene and results from a T to C … (more) The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the TMEM127 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Variants affecting the initiation codon have been identified in individuals with a personal of family history of TMEM127-associated disease (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Eijkelenkamp K et al. Clin GEnet. 2018 May;93(5):1049-1056). Protein functional studies have shown initiation codon loss disrupts TMEM127 function (Yao L et al. JAMA. 2010 Dec;304:2611-9). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Likely pathogenic (Jul 21, 2023)	no assertion criteria provided Method: research	Pheochromocytoma Affected status: yes Allele origin: germline	deCODE genetics, Amgen Accession: SCV004022175.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: The variant NM_017849.4:c.2T>C (chr2:96265380) in TMEM127 was detected in 4 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has not been reported in … (more) The variant NM_017849.4:c.2T>C (chr2:96265380) in TMEM127 was detected in 4 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has not been reported in ClinVar previously. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. (less) Number of individuals with the variant: 6 Ethnicity/Population group: Icelandic

Comment:

The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the TMEM127 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Variants affecting the initiation codon have been identified in individuals with a personal of family history of TMEM127-associated disease (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Eijkelenkamp K et al. Clin GEnet. 2018 May;93(5):1049-1056). Protein functional studies have shown initiation codon loss disrupts TMEM127 function (Yao L et al. JAMA. 2010 Dec;304:2611-9). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The variant NM_017849.4:c.2T>C (chr2:96265380) in TMEM127 was detected in 4 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has not been reported in ClinVar previously. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.

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.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_017849.4(TMEM127):c.2T>C (p.Met1Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...