VCV001510878.20 - ClinVar

NM_001231.5(CASQ1):c.1061C>T (p.Ala354Val)

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.

(4)

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
Uncertain significance(3); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001231.5(CASQ1):c.1061C>T (p.Ala354Val)

Variation ID: 1510878 Accession: VCV001510878.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.2 1: 160201246 (GRCh38) [ NCBI UCSC ] 1: 160171036 (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	Mar 28, 2022	Oct 20, 2024	Dec 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001231.5:c.1061C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001222.3:p.Ala354Val	missense
NM_001231.4:c.1061C>T
NC_000001.11:g.160201246C>T
NC_000001.10:g.160171036C>T
NG_042040.1:g.15752C>T

... more HGVS ... less HGVS

Protein change

A354V

Other names

Canonical SPDI

NC_000001.11:160201245: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.

Exome Aggregation Consortium (ExAC) 0.00014

The Genome Aggregation Database (gnomAD), exomes 0.00014

Trans-Omics for Precision Medicine (TOPMed) 0.00015

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

The Genome Aggregation Database (gnomAD) 0.00023

Links

dbSNP: rs147541452 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.
CASQ1		-	-	GRCh38 GRCh37	305	319

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.
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Dec 25, 2023	RCV002014193.19
Myopathy due to calsequestrin and SERCA1 protein overload	Uncertain significance (1)	criteria provided, single submitter	May 17, 2022	RCV002291510.2
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jul 17, 2023	RCV003348758.2

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.
Uncertain significance (May 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy due to calsequestrin and SERCA1 protein overload (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breda Genetics srl Accession: SCV002583842.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: The variant c.1061C>T (p.Ala354Val) in the CASQ1 gene is reported as uncertain in ClinVar (Variation ID: 1510878). The variant is reported with an estimated allele … (more) The variant c.1061C>T (p.Ala354Val) in the CASQ1 gene is reported as uncertain in ClinVar (Variation ID: 1510878). The variant is reported with an estimated allele frequency of 0.0001371 in gnomAD exomes and 0.0001912 in gnomAD genomes, with no homozygous individuals reported. The nucleotide position is conserved across 35 mammalian species (GERP RS: 4.77). In silico analysis indicates that the variant might be damaging. (less)
Uncertain significance (Dec 25, 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: SCV002304154.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the CASQ1 protein (p.Ala354Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the CASQ1 protein (p.Ala354Val). This variant is present in population databases (rs147541452, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CASQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510878). 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 tolerated. 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)
Uncertain significance (Jul 17, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004052303.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Comment: The c.1061C>T (p.A354V) alteration is located in exon 11 (coding exon 11) of the CASQ1 gene. This alteration results from a C to T substitution … (more) The c.1061C>T (p.A354V) alteration is located in exon 11 (coding exon 11) of the CASQ1 gene. This alteration results from a C to T substitution at nucleotide position 1061, causing the alanine (A) at amino acid position 354 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely benign (Jan 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916528.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: CASQ1: BS1:Supporting Number of individuals with the variant: 1

Comment:

The variant c.1061C>T (p.Ala354Val) in the CASQ1 gene is reported as uncertain in ClinVar (Variation ID: 1510878). The variant is reported with an estimated allele frequency of 0.0001371 in gnomAD exomes and 0.0001912 in gnomAD genomes, with no homozygous individuals reported. The nucleotide position is conserved across 35 mammalian species (GERP RS: 4.77). In silico analysis indicates that the variant might be damaging.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the CASQ1 protein (p.Ala354Val). This variant is present in population databases (rs147541452, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CASQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510878). 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 tolerated. 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.

Comment:

The c.1061C>T (p.A354V) alteration is located in exon 11 (coding exon 11) of the CASQ1 gene. This alteration results from a C to T substitution at nucleotide position 1061, causing the alanine (A) at amino acid position 354 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs147541452 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001231.5(CASQ1):c.1061C>T (p.Ala354Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147541452 ...