rs121913624

chr14-23429278-C-Achr14-23429278-C-Gchr14-23429278-C-T

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.77

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23429278-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14087. Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 14:23429278-C>A is Pathogenic according to our data. Variant chr14-23429278-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 14101. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23429278-C-A is described in Lovd as [Pathogenic]. Variant chr14-23429278-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1208G>T	p.Arg403Leu	missense_variant	13/40	ENST00000355349.4
MYH7	XM_017021340.2	c.1208G>T	p.Arg403Leu	missense_variant	12/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1208G>T	p.Arg403Leu	missense_variant	13/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 31006259, 27532257, 15386449, 12707239, 18227814, 24566549, 7731997, 7848420, 8254035) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 16, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg403Leu (c.1208G>T) in MYH7 Based on the data reviewed below we consider this variant likely disease-associated. The variant has been seen in at least 3 unrelated cases of HCM with strong segregation data. The variant was first reported by Dausse et al (1993) in a large kindred in which linkage studies including 11 affected relatives pointed towards MYH7. Sequencing of MYH7 identified p.Arg403Leu and its presence was confirmed in 6 affected individuals. A subsequent publication that included some of the same authors reported an additional family that appears to be distinct from the initial report (Al-Mahdawi et al 1994). Three affected individuals and one obligate carrier carried p.Arg403Leu. Richard et al (2003) reported the variant in one individual with HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Gln and p.Arg403Trp, both very likely disease cuausing) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5150 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Gln is not listed in dbSNP (as of 1/14/2012). The variant was not observed in the following published control samples: 50 (Al-Mahdawi et al 1994), 100 (Richard et al 2003). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2021

This sequence change replaces arginine with leucine at codon 403 of the MYH7 protein (p.Arg403Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8254035, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14101). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2020

The p.R403L pathogenic mutation (also known as c.1208G>T), located in coding exon 11 of the MYH7 gene, results from a G to T substitution at nucleotide position 1208. The arginine at codon 403 is replaced by leucine, an amino acid with dissimilar properties, and is located in the head domain. This variant has been reported in several unrelated individuals with hypertrophic cardiomyopathy (HCM), and has been reported to segregate with disease in families (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; al-Mahdawi S et al. Br Heart J, 1994 Aug;72:105-11; Santos S et al. BMC Med. Genet. 2012 Mar;13:17; Walsh R et al. Genet. Med., 2017 02;19:192-203; Cui H et al. Orphanet J Rare Dis. 2019 11;14(1):252; Norrish G et al. Circulation, 2019 07;140:184-192). In addition, other pathogenic variants affecting this codon (p.R403Q, c.1208G>A and p.R403W, c.1207C>T) have also been reported in association with HCM (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

D

BayesDel_noAF

Pathogenic

0.38

Cadd

Pathogenic

26

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Pathogenic

0.96

D

MetaRNN

Pathogenic

0.97

D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

2.9

M

MutationTaster

Benign

1.0

D

PrimateAI

Pathogenic

0.89

D

PROVEAN

Pathogenic

-6.1

D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0010

D

Polyphen

1.0

D

Vest4

0.95

MutPred

0.78

Gain of catalytic residue at R403 (P = 5e-04);

MVP

0.96

MPC

2.3

ClinPred

0.99

D

GERP RS

4.0

Varity_R

0.91

gMVP

0.97

Splicing

Find out SpliceAI and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913624; hg19: chr14-23898487;