Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA015373

181267 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 292a4d25-0148-4928-97f4-e6ae23409769

Approved on: 2022-07-30

Published on: 2022-07-30

HGVS expressions

NM_000257.4:c.4828G>C

NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln)

NC_000014.9:g.23416129C>G

CM000676.2:g.23416129C>G

NC_000014.8:g.23885338C>G

CM000676.1:g.23885338C>G

NC_000014.7:g.22955178C>G

NG_007884.1:g.24533G>C

ENST00000355349.4:c.4828G>C

ENST00000355349.3:c.4828G>C

NM_000257.3:c.4828G>C

NR_126491.1:n.390C>G

Uncertain Significance

PP1_Moderate PM2_Supporting PP3 PS4_Supporting

BS4 BS3 BS1 BP3 BP7 BP4 BP5 PS3 PS1 PS2 PM1 PM4 PM5 PM6 PVS1 BA1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln) variant has been identified in 3 individuals with DCM and 2 individuals with HCM (PS4_Supporting; Marston 2015 PMID: 26406308; Minoche 2019 PMID: 29961767; Horvat 2019 PMID: 29892087; GeneDx pers. comm.; Invitae pers. comm). It was also identified in 1 individual with atrial fibrillation (Invitae pers. comm.). This variant has been observed to segregate with DCM in 5 affected relatives of a proband with DCM as well as not segregate with DCM in an affected maternal uncle, although this discrepancy may be explained by the presence of an environmental origin of disease. (PP1_moderate; Minoche 2019 PMID: 29961767; Horvat 2019 PMID: 29892087). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1_Moderate; PM2_Supporting; PP3.

PP1_Moderate

Segregates in 5 family members affected with DCM in PMID 29961767

PM2_Supporting

Variant not in gnomAD. Good coverage

PP3

In silico analysis programs (SIFT, PolyPhen2, Mutation Taster) predict this variant to have an impact on the protein function. Revel score suggest impact

PS4_Supporting

Identified in 3 probands with DCM, 2 probands with HCM - Also identified in one patient with atrial fibrillation and possible noncompaction cardiomyopathy (not counted towards the total). - Segregated with DCM in 5 affected relatives in one family- in this same family, variant did not segregate with one family member affected with DCM.

BS4

Did not segregate in one family member with DCM in PMID: 29961767 (only one family member, so does not meet?)

BS3

Function studies for this variant are not available in the published literature.

BS1

Variant not in gnomAD.

BP3

This is a missense variant.

BP7

This is a missense variant.

BP4

In silico analysis programs (SIFT, PolyPhen2, Mutation Taster) predict this variant to have an impact on the protein function.

BP5

not applicable to this variant

PS3

Function studies for this variant are not available in the published literature.

PS1

Pathogenic variants at the same amino acid residue have not been previously reported.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Variant is not located in a mutational hot spot and/or critical and well-established functional domain.

PM4

This is a missense variant and is not known to change the length of the protein.

PM5

Pathogenic variants at the same amino acid residue have not been previously reported.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PVS1

This is a missense variant.

BA1

Variant not in gnomAD.

Curation History

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