NM_198271.5:c.1259T>C

Variant names:

• chr3-69119096-A-G
• rs1553687786
• NM_198271.5:c.1259T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198271.5(LMOD3):​c.1259T>C​(p.Leu420Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.62
• Publications: 0 publications found

Genes affected

LMOD3 (HGNC:6649): (leiomodin 3) The protein encoded by this gene is a member of the leiomodin family of proteins. This protein contains three actin-binding domains, a tropomyosin domain, a leucine-rich repeat domain, and a Wiskott-Aldrich syndrome protein homology 2 domain (WH2). Localization of this protein to the pointed ends of thin filaments has been observed, and there is evidence that this protein acts as a catalyst of actin nucleation, and is important to the organization of sarcomeric thin filaments in skeletal muscles. Mutations in this gene have been associated as one cause of Nemaline myopathy, as other genes have also been linked to this disorder. Nemaline myopathy is a disorder characterized by nonprogressive generalized muscle weakness and protein inclusions (nemaline bodies) in skeletal myofibers. Patients with mutations in this gene often present with a severe congenital form of the disorder. [provided by RefSeq, Jan 2015]

LMOD3 Gene-Disease associations (from GenCC):

• nemaline myopathy 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.1259T>C	p.Leu420Ser	missense_variant	Exon 2 of 3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.1259T>C	p.Leu420Ser	missense_variant	Exon 3 of 4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.1259T>C	p.Leu420Ser	missense_variant	Exon 2 of 3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.1259T>C	p.Leu420Ser	missense_variant	Exon 3 of 4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.1259T>C	p.Leu420Ser	missense_variant	Exon 3 of 4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 10 Uncertain:1

Jul 15, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with serine at codon 420 of the LMOD3 protein (p.Leu420Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMOD3-related disease. ClinVar contains an entry for this variant (Variation ID: 475299). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	.;.;T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;M
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.052	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.76
MutPred		0.21		Loss of glycosylation at K415 (P = 0.0568);Loss of glycosylation at K415 (P = 0.0568);Loss of glycosylation at K415 (P = 0.0568);
MVP		0.62
MPC		0.18
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.66
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553687786; hg19: chr3-69168247; COSMIC: COSV101341984;