ClinVar Genomic variation as it relates to human health
NM_016648.4(LARP7):c.320C>T (p.Thr107Ile)
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.
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.
Uncertain significance(7); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016648.4(LARP7):c.320C>T (p.Thr107Ile)
Variation ID: 218568 Accession: VCV000218568.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q25 4: 112646604 (GRCh38) [ NCBI UCSC ] 4: 113567760 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 27, 2015 Oct 20, 2024 Sep 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016648.4:c.320C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057732.2:p.Thr107Ile missense NM_001267039.4:c.320C>T NP_001253968.2:p.Thr107Ile missense NM_001370974.1:c.320C>T NP_001357903.1:p.Thr107Ile missense NM_001370975.1:c.320C>T NP_001357904.1:p.Thr107Ile missense NM_001370976.1:c.320C>T NP_001357905.1:p.Thr107Ile missense NM_001370977.1:c.320C>T NP_001357906.1:p.Thr107Ile missense NM_001370978.1:c.320C>T NP_001357907.1:p.Thr107Ile missense NM_001370979.1:c.320C>T NP_001357908.1:p.Thr107Ile missense NM_001370980.1:c.320C>T NP_001357909.1:p.Thr107Ile missense NM_001370981.1:c.83C>T NP_001357910.1:p.Thr28Ile missense NM_001370982.1:c.83C>T NP_001357911.1:p.Thr28Ile missense NM_015454.3:c.320C>T NP_056269.1:p.Thr107Ile missense NM_016648.3:c.320C>T NC_000004.12:g.112646604C>T NC_000004.11:g.113567760C>T NG_032779.1:g.14641C>T - Protein change
- T107I, T28I
- Other names
- p.Thr114Ile
- Canonical SPDI
- NC_000004.12:112646603:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00026
The Genome Aggregation Database (gnomAD) 0.00026
The Genome Aggregation Database (gnomAD), exomes 0.00032
Trans-Omics for Precision Medicine (TOPMed) 0.00038
Exome Aggregation Consortium (ExAC) 0.00058
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 | ||
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HI score
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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. |
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LARP7 | - | - |
GRCh38 GRCh37 |
120 | 297 |
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. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 25, 2023 | RCV000202866.3 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Feb 27, 2024 | RCV000998258.31 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Sep 20, 2024 | RCV002280110.9 |
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. |
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Uncertain significance
(Dec 31, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000257861.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
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Uncertain significance
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Microcephalic primordial dwarfism, Alazami type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768658.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Alazami syndrome. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a recessive condition (138 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated La RNA-binding domain (PMID: 25753663). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant was identified compound heterozygous in an individual with Alazami syndrome and was regarded as likely pathogenic (ClinVar). However, this variant has been classified multiple times as a VUS in unrelated individuals (ClinVar) and also as likely benign (LOVD) by diagnostic laboratories. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_015454.2(LARP7):c.290C>A; p.(Ser97*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005190230.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
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Uncertain significance
(Jun 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001154225.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002122233.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 107 of the LARP7 protein (p.Thr107Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 107 of the LARP7 protein (p.Thr107Ile). This variant is present in population databases (rs200393300, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with LARP7-related conditions. ClinVar contains an entry for this variant (Variation ID: 218568). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LARP7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029163.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: LARP7 c.320C>T (p.Thr107Ile) results in a non-conservative amino acid change located in the La-type HTH domain (IPR006630) of the encoded protein sequence. Three … (more)
Variant summary: LARP7 c.320C>T (p.Thr107Ile) results in a non-conservative amino acid change located in the La-type HTH domain (IPR006630) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 233580 control chromosomes. This frequency does not allow for any conclusion about variant significance. To our knowledge, no occurrence of c.320C>T in individuals affected with Microcephalic Primordial Dwarfism, Alazami Type and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four classified the variant as uncertain significance, and one classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001997562.4
First in ClinVar: Nov 06, 2021 Last updated: Oct 08, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
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Likely benign
(Sep 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Microcephalic primordial dwarfism, Alazami type
Affected status: no
Allele origin:
germline
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3billion
Accession: SCV005328586.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous … (more)
The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. (less)
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Likely pathogenic
(Jun 15, 2022)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Clinical significance appears to be a case-level interpretation inconsistent with variant classification
Source: ClinGen
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Microcephalic primordial dwarfism, Alazami type
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV002568421.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
Upon physical exam this individual was confirmed to clinically have Alazami syndrome. Also found to have telomere shortening (< 10%) by RepeatDx.
Number of individuals with the variant: 1
Clinical Features:
Small for gestational age (present) , Decreased fetal movement (present) , Breech presentation (present) , Abnormal delivery (present) , Poor suck (present) , Prolonged neonatal … (more)
Small for gestational age (present) , Decreased fetal movement (present) , Breech presentation (present) , Abnormal delivery (present) , Poor suck (present) , Prolonged neonatal jaundice (present) , Caesarian section (present) , Secondary Caesarian section (present) , Ectopic kidney (present) , High palate (present) , Malar flattening (present) , Short philtrum (present) , Macrotia (present) , Recurrent otitis media (present) , Prominent nose (present) , Hypermetropia (present) , Horizontal nystagmus (present) , Eczematoid dermatitis (present) , Atopic eczema (present) , Plagiocephaly (present) , Failure to thrive (present) , Gastroesophageal reflux (present) , Developmental regression (present) , Scoliosis (present) , Severe muscular hypotonia (present) , Unilateral ptosis (present) , Congenital bilateral hip dislocation (present) , Axial hypotonia (present) , Aplasia/Hypoplasia of the cerebral white matter (present) , Abnormal brain morphology (present) , Profound global developmental delay (present) , Hip subluxation (present) (less)
Age: 10-19 years
Sex: male
Tissue: blood
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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
HelpTitle | Author | Journal | Year | Link |
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Structural insight into the mechanism of stabilization of the 7SK small nuclear RNA by LARP7. | Uchikawa E | Nucleic acids research | 2015 | PMID: 25753663 |
Text-mined citations for rs200393300 ...
HelpRecord last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.