NM_145207.3(AFG2A):c.1A>C (p.Met1Leu) AND Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 17, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000652795.12

Allele description [Variation Report for NM_145207.3(AFG2A):c.1A>C (p.Met1Leu)]

NM_145207.3(AFG2A):c.1A>C (p.Met1Leu)

Gene:

AFG2A:AFG2 AAA ATPase homolog A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q28.1

Genomic location:

Preferred name:

NM_145207.3(AFG2A):c.1A>C (p.Met1Leu)

Other names:

p.M1?:ATG>CTG

HGVS:

NC_000004.12:g.122923143A>C
NG_030404.1:g.4862T>G
NG_051570.1:g.5074A>C
NM_001317799.2:c.1A>C
NM_001345856.2:c.1A>C
NM_145207.3:c.1A>CMANE SELECT
NP_001304728.1:p.Met1Leu
NP_001332785.1:p.Met1Leu
NP_660208.2:p.Met1Leu
NC_000004.11:g.123844298A>C
NM_145207.2:c.1A>C

Protein change:

M1L

Links:

dbSNP: rs552219028

NCBI 1000 Genomes Browser:

rs552219028

Molecular consequence:

NM_001317799.2:c.1A>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001345856.2:c.1A>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_145207.3:c.1A>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001317799.2:c.1A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001345856.2:c.1A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145207.3:c.1A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (NEDHSB)
Synonyms:: NEURODEVELOPMENTAL DISORDER WITH HEARING LOSS, SEIZURES, AND BRAIN ABNORMALITIES
Identifiers:: MONDO: MONDO:0014698; MedGen: C4225276; Orphanet: 457351; OMIM: 616577

Recent activity

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hypothetical protein A5CPYCFAH4_03380 [Alistipes onderdonkii subsp. vulgaris]
hypothetical protein A5CPYCFAH4_03380 [Alistipes onderdonkii subsp. vulgaris]
gi|1681981693|dbj|BBL08114.1|

Protein
E.coli xth gene encoding exonuclease III, complete cds
E.coli xth gene encoding exonuclease III, complete cds
gi|148276|gb|M22592.1|ECOXTH

Nucleotide
R.norvegicus mRNA encoding 45kDa protein which binds to heymann nephritis antige...
R.norvegicus mRNA encoding 45kDa protein which binds to heymann nephritis antigen gp330
gi|55551|emb|Z11995.1|

Nucleotide
Klebsiella sp. 93934 NODE_119_length_559_cov_55.097510, whole genome shotgun seq...
Klebsiella sp. 93934 NODE_119_length_559_cov_55.097510, whole genome shotgun sequence
gi|2693634509|ref|NZ_JAWJPU01000011 gnl|WGS:NZ_JAWJPU01|NODE_119_length_559_cov_55.097510

Nucleotide
Klebsiella sp. 93934 NODE_122_length_533_cov_96.381579, whole genome shotgun seq...
Klebsiella sp. 93934 NODE_122_length_533_cov_96.381579, whole genome shotgun sequence
gi|2693634512|ref|NZ_JAWJPU01000012 gnl|WGS:NZ_JAWJPU01|NODE_122_length_533_cov_96.381579

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000774666	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 9, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30552426, 28492532
SCV001745323	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Likely pathogenic (May 6, 2021)	germline	clinical testing
SCV005086726	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30552426, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000774666

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 9, 2022)

germline

clinical testing

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

SCV001745323

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

no assertion criteria provided

Likely pathogenic
(May 6, 2021)

germline

clinical testing

SCV005086726

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.

Papuc SM, Abela L, Steindl K, Begemann A, Simmons TL, Schmitt B, Zweier M, Oneda B, Socher E, Crowther LM, Wohlrab G, Gogoll L, Poms M, Seiler M, Papik M, Baldinger R, Baumer A, Asadollahi R, Kroell-Seger J, Schmid R, Iff T, Schmitt-Mechelke T, et al.

Eur J Hum Genet. 2019 Mar;27(3):408-421. doi: 10.1038/s41431-018-0299-8. Epub 2018 Dec 14.

PubMed [citation]

PMID:: 30552426
PMCID:: PMC6460568

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000774666.6

#	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 affects the initiator methionine of the SPATA5 mRNA. The next in-frame methionine is located at codon 75. This variant is present in population databases (rs552219028, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 30552426). ClinVar contains an entry for this variant (Variation ID: 203533). 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.

#	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

From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV001745323.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086726.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (MIM#616577). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 27 heterozygotes, 0 homozygotes). (SP) 0311 - Multiple alternative nucleotide changes at the initiation codon are present in gnomAD (highest allele count in v2: 5 heterozygotes, 0 homozygotes). (I) 0710 - Other variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.1A>T and c.1A>G are predicted to result in a loss of the canonical translation initiation codon, and have been reported as VUS by a clinical testing laboratory in individuals without a second variant that is pathogenic, likely pathogenic or VUS in SPATA5 (ClinVar, personal communication). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as compound heterozygous in two affected individuals, one with encephalopathy and seizures, the other with clinical features including global developmental delay and hearing impairment (PMID: 30552426, DDD study). This variant has also been reported by multiple clinical testing laboratories as likely pathogenic or pathogenic (ClinVar). In addition, it has been reported as a VUS by a clinical testing laboratory in individuals without a second variant that is pathogenic, likely pathogenic or VUS in SPATA5 (ClinVar, personal communication). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Oct 20, 2024

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