VCV000447685.16 - ClinVar

NM_000426.4(LAMA2):c.3924+2T>C

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.

(9)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000426.4(LAMA2):c.3924+2T>C

Variation ID: 447685 Accession: VCV000447685.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q22.33 6: 129315952 (GRCh38) [ NCBI UCSC ] 6: 129637097 (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	Apr 4, 2013	May 7, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000426.4:c.3924+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001079823.2:c.3924+2T>C		splice donor
NC_000006.12:g.129315952T>C
NC_000006.11:g.129637097T>C
NG_008678.1:g.437812T>C
LRG_409:g.437812T>C
LRG_409t1:c.3924+2T>C

... more HGVS ... less HGVS

Protein change

Other names

IVS25, T-C, +2

Canonical SPDI

NC_000006.12:129315951:T:C

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

ClinGen: CA365613577 OMIM: 156225.0003 dbSNP: rs1554269966 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.
LAMA2		-	-	GRCh38 GRCh37	4893	5082

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.
Congenital muscular dystrophy due to partial LAMA2 deficiency	Pathogenic (1)	no assertion criteria provided	May 1, 1997	RCV000015363.25
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 29, 2019	RCV000518321.9
Merosin deficient congenital muscular dystrophy	Pathogenic (2)	criteria provided, single submitter	-	RCV000853232.2
Muscular dystrophy, limb-girdle, autosomal recessive 23	Pathogenic (1)	no assertion criteria provided	Sep 15, 2019	RCV000985057.1
Muscular dystrophy, congenital, merosin deficient or partially deficient	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004527387.2
LAMA2-related muscular dystrophy	Pathogenic (1)	criteria provided, single submitter	Jun 20, 2022	RCV001857909.6

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.
Pathogenic (Dec 13, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613967.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (2) PubMed: 9158149‚ 25525159
Pathogenic (Aug 10, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000862900.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (2) PubMed: 22166137‚ 9158149 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LAMA2 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Merosin deficient congenital muscular dystrophy Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996286.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Number of individuals with the variant: 4 Ethnicity/Population group: Arab Geographic origin: Middle East
Pathogenic (Jul 29, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714786.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (3) PubMed: 25525159‚ 9158149‚ 22166137 Comment: PVS1, PS4_moderate, PM2, PP3 Number of individuals with the variant: 1
Pathogenic (Jun 20, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	LAMA2-related muscular dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002158597.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 9158149‚ 22166137 Comment: For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 26, … (more) For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 26, but is expected to preserve the integrity of the reading-frame (PMID: 9158149). Studies have shown that disruption of this splice site alters LAMA2 gene expression (PMID: 22166137). ClinVar contains an entry for this variant (Variation ID: 447685). This variant is also known as 3973+2T>C. Disruption of this splice site has been observed in individual(s) with congenital muscular dystrophy (PMID: 9158149, 22166137). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the LAMA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy, congenital, merosin deficient or partially deficient Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005038874.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024
Pathogenic (May 01, 1997)	no assertion criteria provided Method: literature only	MUSCULAR DYSTROPHY, CONGENITAL, DUE TO PARTIAL LAMA2 DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035624.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 9158149 Comment on evidence: In 2 sibs with mild congenital merosin-deficient muscular dystrophy (607855) in a consanguineous Saudi Arabian family, Allamand et al. (1997) found that the laminin alpha-2 … (more) In 2 sibs with mild congenital merosin-deficient muscular dystrophy (607855) in a consanguineous Saudi Arabian family, Allamand et al. (1997) found that the laminin alpha-2 chain had an internal deletion as the result of a splice site mutation in the LAMA2 gene that caused the splicing out of exon 25. The predicted protein lacked 63 amino acids in domain IVa, which forms a globular structure on the short arm of the alpha-2 chain. Antibodies against the G-domain of the laminin alpha-2 chain showed a near normal expression in skeletal muscle, whereas antibodies against the N-terminal region showed a drastic reduction. These patients appeared mildly affected compared to others who completely lacked this protein. Allamand et al. (1997) compared the situation to Becker muscular dystrophy (300376), in which in-frame deletions of the dystrophin gene (300377) result in the expression of a semifunctional protein and leads to a mild phenotype. The splice site mutation was a T-to-C transition at position +2 of the consensus donor splice site of exon 25. This mutation was found in homozygous state in both patients and induced the splicing out of exon 25 by alternately using the donor splice site of exon 24. Both parents were heterozygous. (less)
Pathogenic (Sep 15, 2019)	no assertion criteria provided Method: clinical testing	Muscular dystrophy, limb-girdle, autosomal recessive 23 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132998.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020
Pathogenic (Sep 26, 2019)	no assertion criteria provided Method: clinical testing	Merosin deficient congenital muscular dystrophy Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001133036.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020

Comment:

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 26, but is expected to preserve the integrity of the reading-frame (PMID: 9158149). Studies have shown that disruption of this splice site alters LAMA2 gene expression (PMID: 22166137). ClinVar contains an entry for this variant (Variation ID: 447685). This variant is also known as 3973+2T>C. Disruption of this splice site has been observed in individual(s) with congenital muscular dystrophy (PMID: 9158149, 22166137). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the LAMA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

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
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2.	Di Blasi C	BMC research notes	2011	PMID: 22166137
Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain.	Allamand V	Human molecular genetics	1997	PMID: 9158149
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LAMA2	-	-	-	-

Text-mined citations for rs1554269966 ...

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_000426.4(LAMA2):c.3924+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554269966 ...