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.5647G>A (p.Glu1883Lys)

CA016328

14121 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a028f459-e85d-4cf0-be63-4a0532d0ddc4

HGVS expressions

NM_000257.4:c.5647G>A

NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys)

ENST00000355349.4:c.5647G>A

ENST00000355349.3:c.5647G>A

NM_000257.3:c.5647G>A

NC_000014.9:g.23414015C>T

CM000676.2:g.23414015C>T

NC_000014.8:g.23883224C>T

CM000676.1:g.23883224C>T

NC_000014.7:g.22953064C>T

NG_007884.1:g.26647G>A

Uncertain Significance

PS4_Supporting PP3 PM2

PS2 PS1 PS3 BA1 PP1 PVS1 PM6 PM1 PM4 PM5 PM3 BS3 BS4 BS1 BP5 BP2 BP7 BP4 BP3

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys) The c.5647G>A (p.Glu1883Lys) variant in MYH7 has been reported in the homozygous state in 1 individual from a consanguineous family with myosin storage myopathy, HCM and a family history consistent with recessive inheritance (Tajharghi 2007 PMID 17372140) and in 4 individuals with HCM from testing laboratories (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has been identified in 0.01% (1/18716) of African/African American chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but absent from all other populations (PM2). In vitro functional studies provide conflicting evidence on the impact of this on protein function, with some suggesting a potential impact (Viswanathan 2017 PMID: 28973424; Armel 2009 PMID: 19336582), while another suggests that it has a similar function as its wild time counterpart (Dahl-Halvarsson PMID 28125727). Therefore, this data is currently insufficient to establish functional impact and apply PS3. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.

PS4_Supporting

variant was reported in 4 apparently unrelated individuals with hypertrophic cardiomyopathy (internal laboratories data from the ClinGen CMP working group). Genedx: 2, LMM :1, OMGL :

PP3

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

PM2

1/8716 in Africans and 1/31396 in total

PS2

no de novo occurrences reported

PS1

No other variants detected at this codon

PS3

Functional studies (in vivo using C. Elegans, Drosophilia, and biochemical assays) reported conflicting data to determine the effect of this variant on the protein, with some showing a potential biological impact (PMID 28973424 , 19336582 referred as “p.Glu1886Lys”), and some showing function similar to wild-type (PMID 28125727).

BA1

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

PP1

No segregation data

PVS1

n/a

PM6

no de novo occurrences reported

PM1

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

PM4

n/a

PM5

No other variants detected at this codon

PM3

n/a

BS3

see below

BS4

No segregation data

BS1

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

BP5

n/a

BP2

n/a

BP7

n/a

BP4

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

BP3

n/a

Approved on: 2021-07-26

Published on: 2021-07-26

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