VCV000802593.7 - ClinVar

NM_145868.2(ANXA11):c.118G>T (p.Asp40Tyr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_145868.2(ANXA11):c.118G>T (p.Asp40Tyr)

Variation ID: 802593 Accession: VCV000802593.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.3 10: 80170853 (GRCh38) [ NCBI UCSC ] 10: 81930609 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 11, 2020	Jun 9, 2024	Dec 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_145868.2:c.118G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_665875.1:p.Asp40Tyr	missense
NM_001157.3:c.118G>T	NP_001148.1:p.Asp40Tyr	missense
NM_001278407.2:c.118G>T	NP_001265336.1:p.Asp40Tyr	missense
NM_001278408.2:c.118G>T	NP_001265337.1:p.Asp40Tyr	missense
NM_001278409.2:c.19G>T	NP_001265338.1:p.Asp7Tyr	missense
NM_145869.2:c.118G>T	NP_665876.1:p.Asp40Tyr	missense
NC_000010.11:g.80170853C>A
NC_000010.10:g.81930609C>A

... more HGVS ... less HGVS

Protein change

D40Y, D7Y

Other names

p.D40Y

Canonical SPDI

NC_000010.11:80170852:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 602572.0004 dbSNP: rs368751524 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ANXA11		-	-	GRCh38 GRCh37	296	384

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Amyotrophic lateral sclerosis type 23	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV000988396.2
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 7, 2022	RCV002549708.3
Inclusion body myopathy and brain white matter abnormalities	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV001836926.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Amyotrophic lateral sclerosis type 23 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138099.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inclusion body myopathy and brain white matter abnormalities Affected status: yes Allele origin: unknown	3billion Accession: SCV003841270.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (2) PubMed: 34048612‚ 28469040 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism.Same nucleotide change resulting in same amino acid change … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism.Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ANXA11 related disorder (ClinVar ID: VCV000802593). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 34048612 / 3billion dataset). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 34048612). A different missense change at the same codon (p.Asp40Gly) has been reported to be associated with ANXA11 related disorder (ClinVar ID: VCV000488353 / PMID: 28469040). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Scapular winging (present) , Muscle weakness (present) , Weakness of facial musculature (present) , Limb-girdle muscle weakness (present) , Gowers sign (present)
Pathogenic (Apr 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003012444.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 28469040‚ 29845112‚ 33087501‚ 34048612 Comment: This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the … (more) This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp40 amino acid residue in ANXA11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28469040, 29845112, 33087501). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 802593). This missense change has been observed in individuals with ANXA11-related conditions (PMID: 34048612). It has also been observed to segregate with disease in related individuals. This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 40 of the ANXA11 protein (p.Asp40Tyr). (less)
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inclusion body myopathy and brain white matter abnormalities Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005049755.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic lateral sclerosis type 23 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005049777.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024
Pathogenic (Feb 15, 2022)	no assertion criteria provided Method: literature only	INCLUSION BODY MYOPATHY AND BRAIN WHITE MATTER ABNORMALITIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV002097624.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Publications: PubMed (1) PubMed: 34048612 Comment on evidence: In 11 patients from 3 unrelated Brazilian families with inclusion body myopathy and brain white matter abnormalities (IBMWMA; 619733), Leoni et al. (2021) identified a … (more) In 11 patients from 3 unrelated Brazilian families with inclusion body myopathy and brain white matter abnormalities (IBMWMA; 619733), Leoni et al. (2021) identified a heterozygous c.118G-T transversion (c.118G-T, NM_145869) in the ANXA11 gene, resulting in an asp40-to-tyr (D40Y) substitution in a conserved portion of the N-terminal region that is important for calcium-mediated signaling. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not present in public databases, including gnomAD. It was also not found in 3 Brazilian databases. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed. Patient skeletal muscle biopsies showed ANAX11-immunopositive cytoplasmic inclusions. Leoni et al. (2021) noted that a mutation affecting the same codon (D40G; 602572.0001) had been identified in patients with ALS23 (617839), which developed in 2 of the Brazilian patients. (less)
Pathogenic (Jan 11, 2024)	no assertion criteria provided Method: clinical testing	Inclusion body myopathy and brain white matter abnormalities (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV004812021.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Number of individuals with the variant: 2 Clinical Features: Progressive muscle weakness (present) , Muscular dystrophy (present) , Scapular winging (present) , Weakness of facial musculature (present) , Eyelid laxity (present) Family history: yes Age: 50-59 years Sex: male Tissue: Blood

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism.Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ANXA11 related disorder (ClinVar ID: VCV000802593). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 34048612 / 3billion dataset). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 34048612). A different missense change at the same codon (p.Asp40Gly) has been reported to be associated with ANXA11 related disorder (ClinVar ID: VCV000488353 / PMID: 28469040). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp40 amino acid residue in ANXA11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28469040, 29845112, 33087501). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 802593). This missense change has been observed in individuals with ANXA11-related conditions (PMID: 34048612). It has also been observed to segregate with disease in related individuals. This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 40 of the ANXA11 protein (p.Asp40Tyr).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Novel Multisystem Proteinopathy Caused by a Missense ANXA11 Variant.	Leoni TB	Annals of neurology	2021	PMID: 34048612
ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics.	Nahm M	Science translational medicine	2020	PMID: 33087501
ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia.	Zhang K	Neurology. Genetics	2018	PMID: 29845112
Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.	Smith BN	Science translational medicine	2017	PMID: 28469040

Text-mined citations for rs368751524 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_145868.2(ANXA11):c.118G>T (p.Asp40Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs368751524 ...