NM_144988.4(ALG14):c.220G>A (p.Asp74Asn) AND Congenital myasthenic syndrome 15

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 12, 2023
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:: RCV000539711.7

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:: Congenital myasthenic syndrome 15
Synonyms:: Myasthenic syndrome, congenital, 15, without tubular aggregates
Identifiers:: MONDO: MONDO:0014542; MedGen: C4015596; Orphanet: 353327; Orphanet: 590; OMIM: 616227

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000655552	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28733338, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000655552

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 12, 2023)

germline

clinical testing

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000655552.6

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

Description

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.

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

Last Updated: Oct 8, 2024

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