Submissions for variant NM_144988.4(ALG14):c.422T>G (p.Val141Gly)

gnomAD frequency: 0.00006  dbSNP: rs139005007

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000807861	SCV000947937	uncertain significance	Congenital myasthenic syndrome 15	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 141 of the ALG14 protein (p.Val141Gly). This variant is present in population databases (rs139005007, gnomAD 0.01%). This missense change has been observed in individual(s) with ALG14-related congenital disorder of glycosylation (PMID: 28733338). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 652328). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
SIB Swiss Institute of Bioinformatics	RCV001260485	SCV001571395	uncertain significance	Myopathy, epilepsy, and progressive cerebral atrophy	2021-04-13	criteria provided, single submitter	curation	This variant is interpreted as a variant of uncertain significance for Myopathy, epilepsy, and progressive cerebral atrophy, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3).
Ambry Genetics	RCV002537272	SCV003740567	uncertain significance	Inborn genetic diseases	2022-08-08	criteria provided, single submitter	clinical testing	The c.422T>G (p.V141G) alteration is located in exon 4 (coding exon 4) of the ALG14 gene. This alteration results from a T to G substitution at nucleotide position 422, causing the valine (V) at amino acid position 141 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.008% (21/279808) total alleles studied. The highest observed frequency was 0.013% (17/127076) of European (non-Finnish) alleles. This alteration was seen in the compound heterozygous state with c.220G>A (p.D74N) in two sisters who had similar features of severe muscular hypotonia, progressive atrophy, therapy-refractory epilepsy, congenital contractures, and both died within the first year of life (Schorling, 2017). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000807861	SCV004049472	uncertain significance	Congenital myasthenic syndrome 15	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003344065	SCV004049473	uncertain significance	Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001260485	SCV004049474	uncertain significance	Myopathy, epilepsy, and progressive cerebral atrophy	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV001260485	SCV001437507	pathogenic	Myopathy, epilepsy, and progressive cerebral atrophy	2020-10-05	no assertion criteria provided	literature only