Submissions for variant NM_005559.4(LAMA1):c.8556+1G>A

gnomAD frequency: 0.00011  dbSNP: rs764745270

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV001263560	SCV001441585	pathogenic	Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome		criteria provided, single submitter	clinical testing	The patient was treated with two biparental heterozygous mutations in the gene LAMA1 were found, which can sufficiently explain the phenotype. GRCh37:Chr18:6949099C>T; rs764745270 LAMA1 NM_005559.4:c.8556+1G>A and GRCh37:Chr18:6950964CGAGAGC>A LAMA1 NM_005559.4:c.8208_8214delGCTCTCGinsT; (p.Lys2736_Leu2737del) Evaluation of c.8556+1G>A in LAMA1: The paternal inherited heterozygous transition of C>T at position 6949099 on chromosome 18 was marked with 361 reads covered and has an alternative allele frequency (AAV) of 45% in the index, while the father has a AAV of 48% with a coverage of 80 reads, the cover of the nut at this position is 111 reads and shows the reference allele in 99%. The variant in Intron 59 leads to the loss of the 5' Donor splice and probably to skip of the 159bp (53 amino acids) long exon 59. Bioinformatic prediction programs like Mutation Probe and GERP classify this variant as pathogenic one. According to ACMG guidelines c.8556+1G>A is used in LAMA1 also classified as pathogenic. Classification according to ACMG guidelines from c.8556+1G>A to LAMA1: pathogenic - PVS1: zero variant (intronically within the splice site) in the gene LAMA1, for the loss of function is a known disease mechanism, in association with the Poretti-Boltshauser syndrome - PM2: The variant has been rarely described in population genetic studies (such as GnomAD, Iranome, GME, 1kGP, etc.) and not observed in the homozygous state. - PP3: Bioinformatic prediction programs such as GERP and Mutation Scanner classify this variant as pathogenic.
GeneDx	RCV004774367	SCV005382952	likely pathogenic	not provided	2024-04-18	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31028937, 28726809, 31964843, 26932191)
Fulgent Genetics, Fulgent Genetics	RCV001263560	SCV005654254	likely pathogenic	Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome	2023-12-29	criteria provided, single submitter	clinical testing