VCV002634606.2 - ClinVar

NM_147191.1(MMP21):c.1078C>T (p.Arg360Cys)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_147191.1(MMP21):c.1078C>T (p.Arg360Cys)

Variation ID: 2634606 Accession: VCV002634606.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q26.2 10: 125770493 (GRCh38) [ NCBI UCSC ] 10: 127459062 (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	Nov 20, 2023	May 12, 2024	Sep 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_147191.1:c.1078C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_671724.1:p.Arg360Cys	missense
NC_000010.11:g.125770493G>A
NC_000010.10:g.127459062G>A
NG_052815.2:g.10329C>T
LRG_1307:g.10329C>T
LRG_1307t1:c.1078C>T	LRG_1307p1:p.Arg360Cys

... more HGVS ... less HGVS

Protein change

R360C

Other names

Canonical SPDI

NC_000010.11:125770492: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.

Links

OMIM: 608416.0008 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.
MMP21		-	-	GRCh38 GRCh37	103	171

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.
MMP21-related disorder	Uncertain significance (1)	criteria provided, single submitter	Sep 8, 2022	RCV003392860.4
Heterotaxy, visceral, 7, autosomal	Pathogenic (1)	no assertion criteria provided	May 6, 2024	RCV004540645.1

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 (Sep 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MMP21-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119043.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MMP21 c.1078C>T variant is predicted to result in the amino acid substitution p.Arg360Cys. This variant was reported in the homozygous state in two siblings … (more) The MMP21 c.1078C>T variant is predicted to result in the amino acid substitution p.Arg360Cys. This variant was reported in the homozygous state in two siblings with heterotaxy from a consanguineous family (Family 7, Guimier et al. 2015. PubMed ID: 26437028). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-127459062-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Pathogenic (May 06, 2024)	no assertion criteria provided Method: literature only	HETEROTAXY, VISCERAL, 7, AUTOSOMAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV005043087.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Publications: PubMed (1) PubMed: 26437028 Comment on evidence: In 2 sibs, born of consanguineous Turkish parents, with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified a homozygous c.1078C-T transition (c.1078C-T, NM_147191.1) … (more) In 2 sibs, born of consanguineous Turkish parents, with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified a homozygous c.1078C-T transition (c.1078C-T, NM_147191.1) in the MMP21 gene, resulting in an arg360-to-cys (R360C) substitution in the HX1 domain. The unaffected parents were heterozygous for the mutation. The results were confirmed by linkage analysis and homozygosity mapping. The mutation was not found in the ExAC database (March 2015). Functional studies of the variant and studies of patient cells were not performed. (less)

Comment:

The MMP21 c.1078C>T variant is predicted to result in the amino acid substitution p.Arg360Cys. This variant was reported in the homozygous state in two siblings with heterotaxy from a consanguineous family (Family 7, Guimier et al. 2015. PubMed ID: 26437028). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-127459062-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates.	Guimier A	Nature genetics	2015	PMID: 26437028

Text-mined citations for this variant ...

Record last updated May 19, 2024

ClinVar Genomic variation as it relates to human health

NM_147191.1(MMP21):c.1078C>T (p.Arg360Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...