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]

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Variant: NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn)

CA10587778

264607 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c2b95730-913e-40a6-b399-b0dd580ce0cf

Approved on: 2022-07-31

Published on: 2022-07-31

HGVS expressions

NM_000257.4:c.1633G>A

NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn)

NC_000014.9:g.23427840C>T

CM000676.2:g.23427840C>T

NC_000014.8:g.23897049C>T

CM000676.1:g.23897049C>T

NC_000014.7:g.22966889C>T

NG_007884.1:g.12822G>A

ENST00000355349.4:c.1633G>A

ENST00000355349.3:c.1633G>A

NM_000257.3:c.1633G>A

Uncertain Significance

PS4_Moderate PM2_Supporting PP3 PP1

PVS1 BA1 BS3 BS4 BS1 BP2 BP7 BP4 BP5 BP3 PS3 PS1 PS2 PM4 PM5 PM6 PM1

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.1633G>A (p.Asp545Asn) variant has been identified in cis with with another MYH7 variant (NM_000257.4:c.2863G>A (p.Asp955Asn)) in at least 5 individuals with DCM, two of whom also had LVNC and in isolation in 1 individual with DCM (PS4_Moderate: van den Berg 2010 PMID: 20952769, van Spaendonck-Zwarts 2013 PMID: 23349452, Invitae pers. comm., Ambry pers. comm.). The combination of MYH7 variants were also identified in 1 individual with LVNC (Hoedemaekers 2007 PMID: 17947214) and 1 individual with ARVC (Invitae pers. comm). Additionally, both MYH7 variants segregated with DCM in 3 affected relatives from 1 family (PP1: van den Berg 2010 PMID: 20952769) and with LVNC in 4 affected relatives from another family (Hoedemaekers 2007 PMID: 17947214). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. This variant was identified in 0.0003% (FAF 95% CI; 2/113730) of European chromosomes by gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org). 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. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes (Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Based on the majority of available evidence to date, this variant has been observed primarily in cis with MYH7 p.Asp955Asn and has rarely been reported in isolation; therefore, the clinical significance of the p.Asp545Asn variant alone is unclear. 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_Moderate, PP1, PM2_Supporting, PP3.

PS4_Moderate

Abbassi et al PMID:27066506 and Chang PMID:20965760 publication in ClinVar were reviewed but not counted. One was a literature review of published reports and the other was on a TPM1 variant and di not have the MYH7 variant In the literature this variant has been reported to co-occur in cis with another missense variant in MYH7, p.Asp955Asn, and for both variants to segregate with disease in at least 7 individuals from 3 apparently unrelated families with DCM, and in 5 individuals from 1 family with non-compaction cardiomyopathy (PMID 17947214, 20952769, 23349452, and 29517769). It has been reported by Invitae in 1 individual with ARVC and 1 individual with DCM (in the latter the p.Asp955Asn variant was also detected). This variant has been reported by Ambry Genetics in 3 unrelated probands with DCM (in 2 of these probands the p.Asp955Asn variant also detected).

PM2_Supporting

Variant allele frequency is 0.0003% in gnomAD, 95% CI. 2/113730 european

PP3

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function.

PP1

7 segregation, 2 families all in cis with asp955asn one with LVNC so not coutngin those

PVS1

This variant is a missense variant not located at a canonical splice site or initiation codon and is not predicted to result in a frameshift.

BA1

Variant allele frequency is 0.0003% in gnomAD, 95% CI. 2/113730 european

BS3

none available

BS4

n/a

BS1

Variant allele frequency is 0.0003% in gnomAD, 95% CI. 2/113730 european

BP2

in cis with asp955asn in almost all individuals

BP7

This is a missense variant.

BP4

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function.

BP5

n/a

BP3

This variant is not predicted to result in an in-frame deletion or insertion.

PS3

none available

PS1

Pathogenic variants have not been previously reported at this protein residue (ClinVar)

PS2

n/a

PM4

This variant is not predicted to result in a protein length change as a result of an in-frame deletion or insertion.

PM5

Pathogenic variants have not been previously reported at this protein residue (ClinVar)

PM6

n/a

PM1

This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes (PM1; Walsh 2017 PMID:27532257).

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