Submissions for variant NM_005559.4(LAMA1):c.7195+2T>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002308633	SCV002600605	likely pathogenic	Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome	2022-10-20	criteria provided, single submitter	clinical testing	Variant summary: LAMA1 c.7195+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). To our knowledge, no occurrence of c.7195+2T>A in individuals affected with Ataxia-Intellectual Disability-Oculomotor Apraxia-Cerebellar Cysts Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002308633	SCV005397438	likely pathogenic	Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (T>A) at position 7195+2 of the coding sequence of the LAMA1 gene in the canonical donor splice site of exon 50. This is a previously reported variant (ClinVar 1723357) that has been observed in a cohort of apparently healthy individuals (PMID: 31964843). This variant is present in 1 of 251482 alleles (0.0004%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this to base change will disrupt the canonical donor splice site, and the T base at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. Given this information, we consider this a likely pathogenic variant. ACMG Criteria: PM2, PVS1