ClinVar Miner

Submissions for variant NM_014462.3(LSM1):c.231+4A>C (rs775468919)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wendy Chung Laboratory,Columbia University Medical Center RCV000766236 SCV000891374 uncertain significance Cryptorchidism; Triphalangeal thumb; Inguinal hernia; Feeding difficulties; Hemivertebrae; Constipation; Oligohydramnios; Hydroureter; Abnormal facial shape; Hypospadias, penile; Strabismus; Intellectual disability; Generalized hypotonia; Mitral stenosis; Fetal pyelectasis; Patent ductus arteriosus after premature birth; Perimembranous ventricular septal defect; Neurodevelopmental delay; Bicuspid aortic valve 2019-01-03 criteria provided, single submitter research 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.
Broad Institute Rare Disease Group,Broad Institute RCV001254677 SCV001430731 uncertain significance Complex neurodevelopmental disorder 2020-05-28 criteria provided, single submitter research 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.
OMIM RCV001253819 SCV001429697 uncertain significance not provided 2020-08-14 no assertion criteria provided literature only

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