VCV000617604.10 - ClinVar

NM_001136035.4(TRMT1):c.1332_1333del (p.Tyr445fs)

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.

(5)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001136035.4(TRMT1):c.1332_1333del (p.Tyr445fs)

Variation ID: 617604 Accession: VCV000617604.10

Type and length

Deletion, 2 bp

Location

Cytogenetic: 19p13.13 19: 13109445-13109446 (GRCh38) [ NCBI UCSC ] 19: 13220259-13220260 (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, 2019	Apr 6, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001136035.4:c.1332_1333del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001129507.1:p.Tyr445fs	frameshift
NM_001136035.4:c.1332_1333delGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001136035.2:c.1332_1333del
NM_001142554.3:c.1245_1246del	NP_001136026.1:p.Tyr416fs	frameshift
NM_001351760.2:c.1245_1246del	NP_001338689.1:p.Tyr416fs	frameshift
NM_001351761.2:c.1224_1225del	NP_001338690.1:p.Tyr409fs	frameshift
NM_001351762.2:c.549_550del	NP_001338691.1:p.Tyr184fs	frameshift
NM_017722.5:c.1332_1333del	NP_060192.1:p.Tyr445fs	frameshift
NC_000019.10:g.13109446_13109447del
NC_000019.9:g.13220260_13220261del
NG_054900.1:g.13122_13123del

... more HGVS ... less HGVS

Protein change

Y409fs, Y416fs, Y445fs, Y184fs

Other names

Canonical SPDI

NC_000019.10:13109444:ACA: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.

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

Links

OMIM: 611669.0003 dbSNP: rs1203487591 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.
TRMT1		-	-	GRCh38 GRCh37	141	173

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.
Intellectual developmental disorder, autosomal recessive 68	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000754767.10

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 (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual developmental disorder, autosomal recessive 68 Affected status: yes Allele origin: germline	3billion Accession: SCV002573229.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 26308914 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26308914). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 26308914). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000617604 / PMID: 26308914). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hepatomegaly (present) , Cerebral atrophy (present) , Recurrent infections (present) , Immunodeficiency (present)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual developmental disorder, autosomal recessive 68 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805636.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Oct 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual developmental disorder, autosomal recessive 68 Affected status: yes Allele origin: biparental	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440429.2 First in ClinVar: Oct 31, 2020 Last updated: Sep 25, 2021	Comment: This variant was identified as homozygous.
Pathogenic (Jan 31, 2019)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 68 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000882657.1 First in ClinVar: Feb 04, 2019 Last updated: Feb 04, 2019	Publications: PubMed (1) PubMed: 26308914 Comment on evidence: In 3 brothers, born of consanguineous Iranian parents (family 9000114), with autosomal recessive intellectual developmental disorder-68 (MRT68; 618302), Davarniya et al. (2015) identified a homozygous … (more) In 3 brothers, born of consanguineous Iranian parents (family 9000114), with autosomal recessive intellectual developmental disorder-68 (MRT68; 618302), Davarniya et al. (2015) identified a homozygous 2-bp deletion (c.1332_1333delGT, NM_001136035.2) in the TRMT1 gene, predicted to result in a frameshift and premature termination (Tyr445LeufsTer28). The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases. It was absent in 100 Iranian controls. Functional studies of the variant and studies of patient cells were not performed. (less)
Pathogenic (May 13, 2021)	no assertion criteria provided Method: clinical testing	Intellectual developmental disorder, autosomal recessive 68 Affected status: yes Allele origin: inherited	Pediatric Genetics Clinic, Sheba Medical Center Accession: SCV001712242.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Clinical Features: Global developmental delay (present) , Hearing impairment (present) , Hypotonia (present) , Strabismus (present) , Thrombocytosis (present) , Prominent fingertip pads (present) , Clinodactyly of … (more) Global developmental delay (present) , Hearing impairment (present) , Hypotonia (present) , Strabismus (present) , Thrombocytosis (present) , Prominent fingertip pads (present) , Clinodactyly of the 5th finger (present) , Joint hypermobility (present) (less) Secondary finding: no

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26308914). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 26308914). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000617604 / PMID: 26308914). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Title	Author	Journal	Year	Link
The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families.	Davarniya B	PloS one	2015	PMID: 26308914

Text-mined citations for rs1203487591 ...

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 Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_001136035.4(TRMT1):c.1332_1333del (p.Tyr445fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1203487591 ...