NM_016648.4(LARP7):c.320C>T (p.Thr107Ile) AND Microcephalic primordial dwarfism, Alazami type

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 20, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV002280110.9

Allele description [Variation Report for NM_016648.4(LARP7):c.320C>T (p.Thr107Ile)]

NM_016648.4(LARP7):c.320C>T (p.Thr107Ile)

Gene:

LARP7:La ribonucleoprotein 7, transcriptional regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q25

Genomic location:

Preferred name:

NM_016648.4(LARP7):c.320C>T (p.Thr107Ile)

Other names:

p.Thr114Ile

HGVS:

NC_000004.12:g.112646604C>T
NG_032779.1:g.14641C>T
NM_001267039.4:c.320C>T
NM_001370974.1:c.320C>T
NM_001370975.1:c.320C>T
NM_001370976.1:c.320C>T
NM_001370977.1:c.320C>T
NM_001370978.1:c.320C>T
NM_001370979.1:c.320C>T
NM_001370980.1:c.320C>T
NM_001370981.1:c.83C>T
NM_001370982.1:c.83C>T
NM_015454.3:c.320C>T
NM_016648.4:c.320C>TMANE SELECT
NP_001253968.2:p.Thr107Ile
NP_001357903.1:p.Thr107Ile
NP_001357904.1:p.Thr107Ile
NP_001357905.1:p.Thr107Ile
NP_001357906.1:p.Thr107Ile
NP_001357907.1:p.Thr107Ile
NP_001357908.1:p.Thr107Ile
NP_001357909.1:p.Thr107Ile
NP_001357910.1:p.Thr28Ile
NP_001357911.1:p.Thr28Ile
NP_056269.1:p.Thr107Ile
NP_057732.2:p.Thr107Ile
NC_000004.11:g.113567760C>T
NM_001267039.1:c.341C>T
NM_015454.2:c.320C>T
NM_016648.3:c.320C>T

Protein change:

T107I

Links:

dbSNP: rs200393300

NCBI 1000 Genomes Browser:

rs200393300

Molecular consequence:

NM_001267039.4:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370974.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370975.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370976.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370977.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370978.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370979.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370980.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370981.1:c.83C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370982.1:c.83C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015454.3:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016648.4:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Microcephalic primordial dwarfism, Alazami type
Synonyms:: FACIAL DYSMORPHISM, INTELLECTUAL DISABILITY, AND PRIMORDIAL DWARFISM; Alazami syndrome
Identifiers:: MONDO: MONDO:0014031; MedGen: C3554439; Orphanet: 319671; OMIM: 615071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002768658	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25753663, 25741868
SCV005328586	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 20, 2024)	germline	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

SCV002768658

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005328586

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Sep 20, 2024)

germline

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	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural insight into the mechanism of stabilization of the 7SK small nuclear RNA by LARP7.

Uchikawa E, Natchiar KS, Han X, Proux F, Roblin P, Zhang E, Durand A, Klaholz BP, Dock-Bregeon AC.

Nucleic Acids Res. 2015 Mar 31;43(6):3373-88. doi: 10.1093/nar/gkv173. Epub 2015 Mar 9.

PubMed [citation]

PMID:: 25753663
PMCID:: PMC4381077

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV002568421.1

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

Description

Upon physical exam this individual was confirmed to clinically have Alazami syndrome. Also found to have telomere shortening (< 10%) by RepeatDx.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768658.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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

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

From 3billion, SCV005328586.1

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

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002568421	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	flagged submission Reason: Clinical significance appears to be a case-level interpretation inconsistent with variant classification Notes: None (ACMG Guidelines, 2015)	Likely pathogenic (Jun 15, 2022)	paternal	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

SCV002568421

Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN

flagged submission

Reason: Clinical significance appears to be a case-level interpretation inconsistent with variant classification

Notes: None

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 15, 2022)

paternal

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine