NM_198576.4(AGRN):c.226G>A (p.Gly76Ser) AND Congenital myasthenic syndrome 8

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 9, 2020
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:: RCV001377978.14

Allele description [Variation Report for NM_198576.4(AGRN):c.226G>A (p.Gly76Ser)]

NM_198576.4(AGRN):c.226G>A (p.Gly76Ser)

Genes:

LOC126805576:P300/CBP strongly-dependent group 1 enhancer GRCh37_chr1:956772-957971 [Gene]
AGRN:agrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.33

Genomic location:

Preferred name:

NM_198576.4(AGRN):c.226G>A (p.Gly76Ser)

HGVS:

NC_000001.11:g.1022225G>A
NG_016346.1:g.7103G>A
NM_001305275.2:c.226G>A
NM_198576.4:c.226G>AMANE SELECT
NP_001292204.1:p.Gly76Ser
NP_940978.2:p.Gly76Ser
LRG_198:g.7103G>A
NC_000001.10:g.957605G>A
NM_198576.3:c.226G>A

Protein change:

G76S

Links:

dbSNP: rs756623659

NCBI 1000 Genomes Browser:

rs756623659

Molecular consequence:

NM_001305275.2:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198576.4:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital myasthenic syndrome 8
Synonyms:: MYASTHENIC SYNDROME, CONGENITAL, DUE TO AGRIN DEFICIENCY; Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects
Identifiers:: MONDO: MONDO:0014052; MedGen: C3808739; Orphanet: 590; OMIM: 615120

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001575441	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 9, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24951643, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001575441

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 9, 2020)

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

Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.

Nicole S, Chaouch A, Torbergsen T, Bauché S, de Bruyckere E, Fontenille MJ, Horn MA, van Ghelue M, Løseth S, Issop Y, Cox D, Müller JS, Evangelista T, Stålberg E, Ioos C, Barois A, Brochier G, Sternberg D, Fournier E, Hantaï D, Abicht A, Dusl M, et al.

Brain. 2014 Sep;137(Pt 9):2429-43. doi: 10.1093/brain/awu160. Epub 2014 Jun 20.

PubMed [citation]

PMID:: 24951643

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001575441.4

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

Description

This sequence change replaces glycine with serine at codon 76 of the AGRN protein (p.Gly76Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs756623659, ExAC 0.002%). This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 24951643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243036). Experimental studies have shown that this variant affects AGRN protein function (PMID: 24951643). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Jun 2, 2024

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