VCV001510947.6 - ClinVar

NM_005186.4(CAPN1):c.221G>A (p.Gly74Asp)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005186.4(CAPN1):c.221G>A (p.Gly74Asp)

Variation ID: 1510947 Accession: VCV001510947.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.1 11: 65182922 (GRCh38) [ NCBI UCSC ] 11: 64950393 (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	Aug 25, 2024	Oct 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005186.4:c.221G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005177.2:p.Gly74Asp	missense
NM_001198868.1:c.221G>A
NM_001198868.2:c.221G>A	NP_001185797.1:p.Gly74Asp	missense
NM_001198869.2:c.221G>A	NP_001185798.1:p.Gly74Asp	missense
NR_040008.2:n.308G>A		non-coding transcript variant
NC_000011.10:g.65182922G>A
NC_000011.9:g.64950393G>A
NG_052817.1:g.6708G>A

... more HGVS ... less HGVS

Protein change

G74D

Other names

Canonical SPDI

NC_000011.10:65182921:G: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.

The Genome Aggregation Database (gnomAD) 0.00026

The Genome Aggregation Database (gnomAD), exomes 0.00033

Trans-Omics for Precision Medicine (TOPMed) 0.00037

Exome Aggregation Consortium (ExAC) 0.00040

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00057

Links

dbSNP: rs201318945 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.
CAPN1		-	-	GRCh38 GRCh37	246	297

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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 4, 2023	RCV002043201.4
Autosomal recessive spastic paraplegia type 76	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 27, 2022	RCV002471217.3

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 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive spastic paraplegia type 76 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767911.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 28566166 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 76 (MIM#616907). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated peptidase C2 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The variant has previously been reported as likely pathogenic in one compound heterozygous individual with hereditary spastic paraplegia, however the variant was in cis with another missense that was also considered to be likely pathogenic (LOVD, PMID: 28566166). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Uncertain significance (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive spastic paraplegia type 76 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002786938.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 23, 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: SCV002301147.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28566166 Comment: This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 74 of the CAPN1 protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 74 of the CAPN1 protein (p.Gly74Asp). This variant is present in population databases (rs201318945, gnomAD 0.07%). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 28566166). ClinVar contains an entry for this variant (Variation ID: 1510947). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 (Oct 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive spastic paraplegia type 76 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835311.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Uncertain significance (Oct 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197381.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 76 (MIM#616907). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated peptidase C2 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The variant has previously been reported as likely pathogenic in one compound heterozygous individual with hereditary spastic paraplegia, however the variant was in cis with another missense that was also considered to be likely pathogenic (LOVD, PMID: 28566166). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 74 of the CAPN1 protein (p.Gly74Asp). This variant is present in population databases (rs201318945, gnomAD 0.07%). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 28566166). ClinVar contains an entry for this variant (Variation ID: 1510947). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Expanding the clinical phenotype of CAPN1-associated mutations: A new case with congenital-onset pure spastic paraplegia.	Travaglini L	Journal of the neurological sciences	2017	PMID: 28566166

Text-mined citations for rs201318945 ...

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_005186.4(CAPN1):c.221G>A (p.Gly74Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201318945 ...