Variant classification summary

NM_000257.3:c.2548G>A

MYH7 · NP_000248.2:p.(Ala850Thr) · NM_000257.3

GRCh37: chr14:23894109 C>T · GRCh38: chr14:23424900 C>T

Gene: MYH7 Transcript: NM_000257.3

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

MYH7

Transcript

NM_000257.3

Protein

NP_000248.2:p.(Ala850Thr)

gnomAD AF

2.4780015413169587e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000257.3:c.2548G>A (p.Ala850Thr) is a missense variant in MYH7 exon 22. It is extremely rare in population databases (gnomAD v2.1 AF 3.98e-6, v4.1 grpmax FAF 7.9e-7), satisfying VCEP PM2 at supporting strength.

2

Codon 850 falls within the VCEP-defined MYH7 missense cluster region (codons 167-931), meeting PM1 at moderate strength per Walsh et al. 2019 (PMID:30696458).

3

REVEL in silico meta-predictor score is 0.809, exceeding the VCEP PP3 threshold of ≥0.70, providing supporting evidence for a deleterious effect. SpliceAI predicts no splice impact.

4

A sister missense variant at the same codon, p.Ala850Asp, was reported as a novel mutation in one HCM patient by Fokstuen et al. 2008 (PMID:18409188), but lacks formal VCEP classification necessary for PM5 application.

5

No functional studies, segregation data, de novo observations, or case-control data were identified for this specific variant in any reviewed publication.

6

The variant has been reported in ClinVar (ID 403207) as Uncertain Significance by 5 clinical laboratories and Likely Pathogenic by 1 (Invitae). No expert panel classification has been assigned. ClinVar review status is 'criteria provided, single submitter' at the aggregate level.

7

Applying the MYH7 VCEP v2.0 classification rules: 1 moderate criterion (PM1) and 2 supporting criteria (PM2_Supporting, PP3) are met. This combination does not satisfy any VCEP Likely Pathogenic rule (minimum: Rule 14 requires 2 moderate + ≥2 supporting; Rule 15 requires 1 moderate + ≥4 supporting). The variant remains a Variant of Uncertain Significance.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYH7 Version 2.0 v2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	MYH7 VCEP specifies PVS1 as not applicable; this is a missense variant (c.2548G>A, p.Ala850Thr), not a null variant.
PS1	Not met	No evidence of a different nucleotide change at codon 850 producing the same amino acid change (p.Ala850Thr).
PS2	Not met	No de novo observation reported for NM_000257.3:c.2548G>A in any reviewed publication or ClinVar submission.
PS3	Not met	No variant-specific functional experimental data identified for c.2548G>A (p.Ala850Thr) in any reviewed publication. Reviewed papers are cohort studies, methods papers, or consensus guidelines without MYH7-specific functional assays.
PS4	Not met	No case-control data available with variant-specific counts for c.2548G>A. Cohort studies reviewed (Walsh et al. 2017, Mazzarotto et al. 2019, Oktay et al. 2023) do not report individual variant frequencies usable for PS4 calculation.
PS5	N/A	No alternative nucleotide change at the same codon producing the same amino acid (p.Ala850Thr) is known.
PM1	Met	Codon 850 lies within the VCEP-defined MYH7 missense cluster region (codons 167-931) per Walsh et al. 2019 (PMID:30696458). This region shows significant enrichment of rare missense variants in HCM case cohorts.	cspec
PM2	Met	Variant is extremely rare in population databases. gnomAD v2.1 NFE AF = 8.79e-6 (1/113,748 alleles), well below the VCEP PM2 threshold of ≤0.00004. Absent from Ashkenazi Jewish and Other subpopulations. gnomAD v4.1 grpmax FAF = 7.9e-7.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	A different missense variant at the same codon (p.Ala850Asp) is reported as a novel mutation in PMID:18409188, absent in 192 controls. However, p.Ala850Asp has not been formally classified as pathogenic or likely pathogenic under VCEP guidelines, so the VCEP PM5 requirement for a classified comparator is not satisfied.	PMID:18409188
PM6	Not met	No assumed or confirmed de novo observation for c.2548G>A identified in any reviewed publication.
PP1	Not met	No segregation data available for this variant in any reviewed publication.
PP2	N/A	VCEP MYH7: not applicable; regional missense enrichment is captured by PM1 instead of PP2 per the specification (Walsh et al. 2019 PMID:30696458).	cspec
PP3	Met	REVEL score 0.809 exceeds the VCEP-recommended threshold of ≥0.70 for PP3 application. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico signal is confined to missense pathogenicity prediction.	revel spliceai cspec
PP4	N/A	VCEP MYH7: not applicable; inherited cardiomyopathies have high locus heterogeneity and non-genetic etiologies, precluding phenotype specificity for a single genetic etiology.	cspec
PP5	N/A	VCEP MYH7: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	gnomAD v4.1 grpmax FAF = 7.9e-7, far below the VCEP BA1 threshold of ≥0.001. Variant is extremely rare in all populations.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax FAF = 7.9e-7, far below the VCEP BS1 threshold of ≥0.0001 for MYH7. No subpopulation approaches the threshold.	gnomad_v4 cspec
BS2	N/A	VCEP MYH7: not applicable; inherited cardiomyopathies display reduced penetrance, variable expressivity, and adult-onset, so observation in a healthy adult does not constitute strong benign evidence.	cspec
BS3	Not met	No functional studies demonstrating a benign effect for c.2548G>A (p.Ala850Thr) identified in any reviewed publication.
BS4	Not met	No non-segregation data reported for this variant. VCEP requires ≥2 non-segregations unlikely to be phenocopies.
BP1	N/A	VCEP MYH7: not applicable; for genes where null variants are a known disease mechanism, pathogenic missense variants have also been reported. Missense variants in MYH7 are an established cause of cardiomyopathy.	cspec
BP2	Not met	No evidence of this variant observed in cis or trans with a pathogenic variant in MYH7 or another cardiomyopathy gene.
BP4	Not met	REVEL score 0.809 is well above the VCEP BP4 threshold of ≤0.40. In silico predictions support a deleterious effect, not a benign one.	revel cspec
BP5	N/A	VCEP MYH7: not applicable; co-occurrence with a pathogenic variant for a non-cardiomyopathy disease does not reduce likelihood of independent pathogenicity for cardiomyopathy.	cspec
BP6	N/A	VCEP MYH7: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	VCEP BP7 applies to synonymous variants and intronic variants outside the splice consensus; this is a missense variant (c.2548G>A, p.Ala850Thr).	cspec

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