Submissions for variant NM_005559.4(LAMA1):c.858+1G>T

gnomAD frequency: 0.00012  dbSNP: rs141914419

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469409	SCV002766289	likely pathogenic	Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome	2022-11-22	criteria provided, single submitter	clinical testing	Variant summary: LAMA1 c.858+1G>T 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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 250980 control chromosomes in the gnomAD database, including 1 homozygote. This homozygous individual is reported as being about 50 years old, and suggests a somewhat mild phenotype (Powell_2021). This frequency does not allow conclusions about variant significance. To our knowledge, no occurrence of c.858+1G>T 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001730413	SCV003271899	likely pathogenic	not provided	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the LAMA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMA1 are known to be pathogenic (PMID: 25105227, 26932191). This variant is present in population databases (rs141914419, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LAMA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1299963). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002539797	SCV003588774	uncertain significance	Inborn genetic diseases	2021-06-03	criteria provided, single submitter	clinical testing	The c.858+1G>T intronic alteration consists of a G to T substitution one nucleotide after exon 6 of the LAMA1 gene. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV002469409	SCV003829139	likely pathogenic	Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome	2022-01-27	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001730413	SCV001979358	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001730413	SCV001980365	likely pathogenic	not provided		no assertion criteria provided	clinical testing