Submissions for variant NM_144988.4(ALG14):c.220G>A (p.Asp74Asn)

gnomAD frequency: 0.00012  dbSNP: rs769114543

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000426296	SCV000532668	uncertain significance	not provided	2017-07-27	criteria provided, single submitter	clinical testing	The D74N variant in the ALG14 gene has been reported previously when present in the homozygous state or when in trans with another variant in affected individuals with severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy (Schorling et al., 2017). The D74N variant is observed in 4/11518 (0.03%) alleles from individuals of Latino background and in 16/66558 (0.02%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The D74N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D74N as a variant of uncertain significance.
Invitae	RCV000539711	SCV000655552	pathogenic	Congenital myasthenic syndrome 15	2023-09-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 74 of the ALG14 protein (p.Asp74Asn). This variant is present in population databases (rs769114543, gnomAD 0.03%). This missense change has been observed in individuals with severe neurodegeneration with myopathic and myasthenic features (PMID: 28733338). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 389968). 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 disruptive.
SIB Swiss Institute of Bioinformatics	RCV001260484	SCV001571393	likely pathogenic	Myopathy, epilepsy, and progressive cerebral atrophy	2021-04-13	criteria provided, single submitter	curation	This variant is interpreted as likely pathogenic 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); For recessive disorders, detected in trans with a pathogenic variant (PM3).
Athena Diagnostics	RCV000426296	SCV002817201	pathogenic	not provided	2020-12-31	criteria provided, single submitter	clinical testing	This variant segregates with disease in multiple families (PMID 28733338). The frequency of this variant in the general population is consistent with being disease causing. (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Revvity Omics, Revvity	RCV000426296	SCV003826167	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing
OMIM	RCV001260484	SCV001437506	pathogenic	Myopathy, epilepsy, and progressive cerebral atrophy	2020-10-05	no assertion criteria provided	literature only