NM_000432.4(MYL2):c.275-14G>C AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 31, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000213783.8

Allele description [Variation Report for NM_000432.4(MYL2):c.275-14G>C]

NM_000432.4(MYL2):c.275-14G>C

Gene:

MYL2:myosin light chain 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_000432.4(MYL2):c.275-14G>C

HGVS:

NC_000012.12:g.110913338C>G
NG_007554.1:g.12240G>C
NM_000432.4:c.275-14G>CMANE SELECT
LRG_393t1:c.275-14G>C
LRG_393:g.12240G>C
NC_000012.11:g.111351142C>G
NM_000432.3:c.275-14G>C

Links:

dbSNP: rs375703502

NCBI 1000 Genomes Browser:

rs375703502

Molecular consequence:

NM_000432.4:c.275-14G>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272074	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Apr 13, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000717507	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Mar 22, 2017)	germline	clinical testing	Citation Link,
SCV002600851	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Oct 31, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272074

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Apr 13, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000717507

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Mar 22, 2017)

germline

clinical testing

Citation Link,

SCV002600851

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Oct 31, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.

Burstein DS, Gaynor JW, Griffis H, Ritter A, Connor MJO, Rossano JW, Lin KY, Ahrens-Nicklas RC.

Pediatr Res. 2021 May;89(6):1470-1476. doi: 10.1038/s41390-020-1101-5. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32746448
PMCID:: PMC8256333

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272074.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The c.275-14G>C variant in MYL2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 8/10392 of African chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375703502). This variant is located in the 3' splice region. Computational too ls do not suggest an impact to splicing; however, this information is not predic tive enough to rule out pathogenicity. In summary, the clinical significance of the c.275-14G>C variant is uncertain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From GeneDx, SCV000717507.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600851.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: MYL2 c.275-14G>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 251456 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYL2 causing Hypertrophic Cardiomyopathy phenotype (7.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.275-14G>C has been reported in the literature as a VUS in a setting of multigene testing in an individual affected with Hypertrophic Cardiomyopathy (e.g. Burstein_2021). This report does not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Three laboratories classified the variant as likely benign and one classified it as VUS. Based on the evidence outlined above, the variant was classified as benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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