This variant is classified as VUS since this is the first report associating a human congenital disorder with the gene but the evidence favors pathogenicity and causality.
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Uncertain significance
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 3
- First in ClinVar:
- Apr 17, 2019
- Most recent Submission:
- Aug 24, 2020
- Last evaluated:
- May 28, 2020
- Accession:
- VCV000623485.5
- Variation ID:
- 623485
- Description:
- single nucleotide variant
Help
NM_014462.3(LSM1):c.231+4A>C
- Allele ID
- 612447
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 8p11.23
- Genomic location
- 8: 38169798 (GRCh38) GRCh38 UCSC
- 8: 38027316 (GRCh37) GRCh37 UCSC
- HGVS
-
Nucleotide Protein Molecular
consequenceNM_014462.3(LSM1):c.231+4A>C MANE Select NM_014462.3:c.231+4A>C MANE Select intron variant NC_000008.11:g.38169798T>G NC_000008.10:g.38027316T>G - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000008.11:38169797:T:G
- Functional consequence
- sequence_variant_affecting_splicing [Sequence Ontology SO:1000071]
- The variant is shown to cause complete loss of the canonical isoform by expression studies. [submitted by Wendy Chung Laboratory, Columbia University Medical Center]
- sequence_variant_affecting_transcript_processing [Sequence Ontology SO:1000070]
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- Exome Aggregation Consortium (ExAC) 0.00007
- Trans-Omics for Precision Medicine (TOPMed) 0.00003
- The Genome Aggregation Database (gnomAD), exomes 0.00008
- Trans-Omics for Precision Medicine (TOPMed) 0.00002
- The Genome Aggregation Database (gnomAD) 0.00003
- Links
- OMIM: 607281.0001
- dbSNP: rs775468919
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Uncertain significance | 1 | criteria provided, single submitter | Jan 3, 2019 | RCV000766236.3 | |
| Uncertain significance | 1 | criteria provided, single submitter | May 28, 2020 | RCV001254677.1 | |
| Uncertain significance | 1 | no assertion criteria provided | Aug 14, 2020 | RCV001253819.1 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 03, 2019)
|
criteria provided, single submitter
Method: research
|
(Autosomal recessive inheritance)
Affected status: yes, no
Allele origin:
inherited
|
Wendy Chung Laboratory, Columbia University Medical Center
Accession: SCV000891374.1
First in ClinVar: Apr 17, 2019 Last updated: Apr 17, 2019 |
Comment:
This variant is classified as VUS since this is the first report associating a human congenital disorder with the gene but the evidence favors pathogenicity … (more)
This variant is classified as VUS since this is the first report associating a human congenital disorder with the gene but the evidence favors pathogenicity and causality. (less)
Observation 1:
Number of individuals with the variant: 2
Zygosity: 2 Homozygote
Family history: yes
Sex: mixed
Tissue: Blood
Comment on evidence:
This variant is seen homozygously in two affected siblings from a single family.
Secondary finding: no
Observation 2:
Number of individuals with the variant: 4
Zygosity: 4 Single Heterozygote
Sex: mixed
Tissue: Blood
Comment on evidence:
This variant is seen homozygously in two affected siblings from a single family.
Secondary finding: no
|
|
|
Uncertain significance
(May 28, 2020)
|
criteria provided, single submitter
Method: research
|
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001430731.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Comment:
The homozygous c.231+4A>C variant in LSM1 was identified by our study in collaboration with the Chung Lab in 2 siblings with multiple congenital anomalies and … (more)
The homozygous c.231+4A>C variant in LSM1 was identified by our study in collaboration with the Chung Lab in 2 siblings with multiple congenital anomalies and global developmental delay (PMID: 31010896). This variant has also been reported as a VUS by the Wendy Chung Laboratory in ClinVar (Variation ID: 623485). This variant has been identified in 0.190% (19/10022) of Ashkenazi Jewish chromosomes and 0.002% (2/113204) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775468919). Although this variant has been seen in the general population, its frequency is not high enough to rule out an impact to the protein. In vitro functional studies with patient peripheral blood provide some evidence that the c.231+4A>C variant may slightly impact protein splicing (PMID: 31010896). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools do suggest a weak impact to splicing. However, this information is not predictive enough to determine impact to the protein. The presence of this variant in affected homozygotes increases the likelihood that the c.231+4A>C variant is pathogenic (PMID: 31010896). Furthermore, although this gene has been reported in association with multiple congenital anomalies and global developmental delay, it currently has limited evidence for these associations. In summary, the clinical significance of the c.231+4A>C variant is uncertain. (less)
|
|
|
Uncertain significance
(Aug 14, 2020)
|
no assertion criteria provided
Method: literature only
|
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001429697.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Comment on evidence:
This variant is classified as a variant of unknown significance because its contribution to global developmental delay with multiple congenital anomalies and abnormal eye movements … (more)
This variant is classified as a variant of unknown significance because its contribution to global developmental delay with multiple congenital anomalies and abnormal eye movements has not been confirmed. In a 13-year-old girl and her 6-year-old brother, who had global developmental delay, multiple congenital anomalies affecting the heart, skeleton, and genitourinary system, and abnormal eye movements, Okur et al. (2019) identified homozygosity for a splicing mutation (c.231+4A-C, NM_014462.3) in the LSM1 gene. Their unaffected nonconsanguineous Ashkenazi Jewish parents were heterozygous for the mutation, as were 2 unaffected sibs. The variant was present in gnomAD in only heterozygous state, predominantly in Ashkenazi Jewish individuals, with an allele frequency of 0.0019 in this population. Bilateral hydronephrosis, congenital heart disease, and vertebral anomalies were detected prenatally in both patients. The boy had bilateral dysplastic kidneys and underwent renal transplantation at age 18 months for end-stage renal disease. He also exhibited left duplicated collecting system, hydroureter, posterior urethral valve obstruction, neurogenic bladder, vesicoureteral reflux, hypospadias, and bilateral inguinal hernia with cryptorchidism. Congenital cardiovascular defects consisted of ventricular septal defect, atrial septal defect, and patent ductus arteriosus in the girl, and mild mitral stenosis, bicuspid aortic valve with partial fusion accompanied by mild aortic stenosis and regurgitation, dilation of the ascending aorta, and mildly tortuous aortic arch with an aberrant right subclavian artery in the boy. Skeletal anomalies included vertebral anomalies in both, and the girl also exhibited triphalangeal thumbs and fifth-finger clinodactyly. Both affected sibs had feeding difficulties requiring gastrostomy tube placement, and both had motor as well as speech delay and impaired intellectual development. Dysmorphic features in the girl included body and facial asymmetry, with the left side smaller than the right; she also had brachycephaly, frontal bossing, cupped ears, hypertelorism, rounded nasal tip, small teeth, and micrognathia. Her brother had cupped right ear, flat nasal bridge, and excess nuchal folds. Both showed abnormal eye function, with strabismus in the girl and dysfunctional saccadic pursuit in the boy. Analysis of whole-blood cDNA from the boy revealed a 134-bp fragment corresponding to noncoding RNA that lacked exon 3; skipping of exon 3 was predicted to cause a frameshift resulting in a truncated 44-amino acid protein, which would lack part of the LSM domain and the remainder of the carboxyl terminus of the 133-amino acid protein. (less)
|
Functional evidence
Help| Functional consequence | Method | Result | Submitter | More information |
|---|---|---|---|---|
|
sequence_variant_affecting_splicing
sequence_variant_affecting_transcript_processing
|
|
|
Wendy Chung Laboratory, Columbia University Medical Center
Accession: SCV000891374.1
First in ClinVar: Apr 17, 2019
Last updated: Apr 17, 2019
|
Comment:
The variant is shown to cause complete loss of the canonical isoform by expression studies.
|
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homozygous noncanonical splice variant in LSM1 in two siblings with multiple congenital anomalies and global developmental delay. | Okur V | Cold Spring Harbor molecular case studies | 2019 | PMID: 31010896 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cbb751bf-ae97-4f59-a067-ec2ab35f063d | - | - | - | - |
Text-mined citations for rs775468919...
HelpThese 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 13, 2023