VCV000666547.2 - ClinVar

NM_001130004.2(ACTN1):c.1349G>A (p.Arg450His)

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.

(2)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001130004.2(ACTN1):c.1349G>A (p.Arg450His)

Variation ID: 666547 Accession: VCV000666547.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.1 14: 68885461 (GRCh38) [ NCBI UCSC ] 14: 69352178 (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	Aug 26, 2019	Feb 28, 2024	Oct 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130004.2:c.1349G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001123476.1:p.Arg450His	missense
NM_001102.4:c.1349G>A	NP_001093.1:p.Arg450His	missense
NM_001130005.2:c.1349G>A	NP_001123477.1:p.Arg450His	missense
NC_000014.9:g.68885461C>T
NC_000014.8:g.69352178C>T
NG_029480.1:g.98906G>A
LRG_886:g.98906G>A
LRG_886t1:c.1349G>A	LRG_886p1:p.Arg450His

... more HGVS ... less HGVS

Protein change

R450H

Other names

Canonical SPDI

NC_000014.9:68885460:C:T

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

dbSNP: rs751173836 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.
ACTN1		-	-	GRCh38 GRCh37	385	397

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.
Platelet-type bleeding disorder 15	Likely pathogenic (1)	criteria provided, single submitter	-	RCV000824966.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 22, 2023	RCV003768547.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Platelet-type bleeding disorder 15 Affected status: yes Allele origin: germline	Hematology laboratory, Robert Debré Hospital Accession: SCV000966142.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (1) PubMed: 31237726 Number of individuals with the variant: 2
Uncertain significance (Oct 22, 2023)	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: SCV004632401.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 31237726 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACTN1 protein (p.Arg450His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACTN1 protein (p.Arg450His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia (PMID: 31237726). ClinVar contains an entry for this variant (Variation ID: 666547). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Not available) indicates that this missense variant is expected to disrupt ACTN1 function with a positive predictive value of 80%. 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. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACTN1 protein (p.Arg450His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia (PMID: 31237726). ClinVar contains an entry for this variant (Variation ID: 666547). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Not available) indicates that this missense variant is expected to disrupt ACTN1 function with a positive predictive value of 80%. 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.

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
Novel ACTN1 variants in cases of thrombocytopenia.	Vincenot A	Human mutation	2019	PMID: 31237726

Text-mined citations for rs751173836 ...

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_001130004.2(ACTN1):c.1349G>A (p.Arg450His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs751173836 ...