NM_144988.4(ALG14):c.220G>A (p.Asp74Asn) AND Myopathy, epilepsy, and progressive cerebral atrophy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 13, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001260484.2

Allele description [Variation Report for NM_144988.4(ALG14):c.220G>A (p.Asp74Asn)]

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

Genes:

ALG14:ALG14 UDP-N-acetylglucosaminyltransferase subunit [Gene - OMIM - HGNC]
ALG14-AS1:ALG14 antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p21.3

Genomic location:

Preferred name:

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

Other names:

ALG14, ASP74ASN (rs769114543)

HGVS:

NC_000001.11:g.95064934C>T
NG_042044.1:g.13018G>A
NM_001305242.2:c.220G>A
NM_144988.4:c.220G>AMANE SELECT
NP_001292171.1:p.Asp74Asn
NP_659425.1:p.Asp74Asn
NC_000001.10:g.95530490C>T
NM_144988.3:c.220G>A

Protein change:

D74N; ASP74ASN

Links:

OMIM: 612866.0004; dbSNP: rs769114543

NCBI 1000 Genomes Browser:

rs769114543

Molecular consequence:

NM_001305242.2:c.220G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_144988.4:c.220G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myopathy, epilepsy, and progressive cerebral atrophy
Identifiers:: MONDO: MONDO:0033619; MedGen: C5436652; OMIM: 619036

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001437506	OMIM	no assertion criteria provided	Pathogenic (Oct 5, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001571393	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 13, 2021)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 28733338, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001437506

OMIM

no assertion criteria provided

Pathogenic
(Oct 5, 2020)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001571393

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 13, 2021)

unknown

curation

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG.

Schorling DC, Rost S, Lefeber DJ, Brady L, Müller CR, Korinthenberg R, Tarnopolsky M, Bönnemann CG, Rodenburg RJ, Bugiani M, Beytia M, Krüger M, van der Knaap M, Kirschner J.

Neurology. 2017 Aug 15;89(7):657-664. doi: 10.1212/WNL.0000000000004234. Epub 2017 Jul 21.

PubMed [citation]

PMID:: 28733338
PMCID:: PMC5562963

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV001437506.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 infants, born of unrelated Dutch parents (family B), with myopathy, epilepsy, and progressive cerebral atrophy (MEPCA; 619036), Schorling et al. (2017) identified a homozygous c.220G-A transition (c.220G-A, NM_144988.3) in exon 2 of the ALG14 gene, resulting in an asp74-to-asn (D74N) substitution. Two infant sisters from an unrelated family of German descent (family A) with the disorder were compound heterozygous for D74N and a c.422T-G transversion in exon 4 of the ALG14 gene, resulting in a val141-to-gly (V141G; 612866.0005). In addition, a similarly affected male infant, born of unrelated Caucasian parents (family C), was compound heterozygous for D74N and a c.326G-A transition in exon 3, resulting in an arg109-to-gln (R109Q; 612866.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. All were found at low frequencies in the ExAC database (less than 0.02%). Functional studies of the variants and studies of patient cells were not performed. The patients presented at birth with severe hypotonia; all died within the first year of life.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV001571393.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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