Submissions for variant NM_144988.4(ALG14):c.136+1G>C

gnomAD frequency: 0.00007  dbSNP: rs150550220

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820147	SCV000960845	uncertain significance	Congenital myasthenic syndrome 15	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 of the ALG14 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ALG14 cause disease. This variant is present in population databases (rs150550220, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALG14-related conditions. ClinVar contains an entry for this variant (Variation ID: 662491). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001546952	SCV001766561	pathogenic	not provided	2024-07-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230600	SCV003928703	uncertain significance	not specified	2023-04-21	criteria provided, single submitter	clinical testing	Variant summary: ALG14 c.136+1G>C 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 the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies and the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ALG14 cause disease. The variant allele was found at a frequency of 7.6e-05 in 251064 control chromosomes (gnomAD). To our knowledge, no occurrence of c.136+1G>C in individuals affected with ALG14-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014and classified the variant as likely pathogenic, and as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586947	SCV005038483	pathogenic	Congenital myopathy	2024-03-01	criteria provided, single submitter	research	PSV1+PM2+PP3