rs199474724

chr1-156134839-G-Achr1-156134839-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_170707.4(LMNA):c.674G>A(p.Arg225Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3 O:1
• Conservation: PhyloP100: 6.87

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156134839-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1364825.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 1-156134839-G-A is Pathogenic according to our data. Variant chr1-156134839-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41234.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_pathogenic=2, Pathogenic=1}. Variant chr1-156134839-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.674G>A	p.Arg225Gln	missense_variant	4/12	ENST00000368300.9
LMNA	NM_005572.4	c.674G>A	p.Arg225Gln	missense_variant	4/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.674G>A	p.Arg225Gln	missense_variant	4/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.674G>A	p.Arg225Gln	missense_variant	4/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 06, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2020	- -

Emery-Dreifuss muscular dystrophy 3, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2012

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the LMNA protein (p.Arg225Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal recessive Emery-Dreifuss muscular dystrophy (PMID: 28688748). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with clinical features of autosomal dominant laminopathy (PMID: 22431096); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 41234). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Abnormality of the musculature Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 17, 2021

This missense variant replaces arginine with glutamine at codon 225 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in homozygosity in five individuals affected with autosomal recessive Emery-Dreifuss muscular dystrophy from two families (PMID: 22431096, 28688748). Of the seven heterozygous individuals from these families, two had a pacemaker implanted at ages 78 and 80; and none of them were reported to be affected with cardiomyopathy. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with autosomal recessive LMNA-associated disorders, but the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 04, 2023

This missense variant replaces arginine with glutamine at codon 225 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in homozygosity in five individuals affected with autosomal recessive Emery-Dreifuss muscular dystrophy from two families (PMID: 22431096, 28688748). Of the seven heterozygous individuals from these families, two had a pacemaker implanted at ages 78 and 80; and none of them were reported to be affected with cardiomyopathy. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with autosomal recessive LMNA-associated disorders, but the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
CardioboostCm	Uncertain	0.78
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.075	T;T;T;T;T;D;D;T;D
Polyphen		0.54	P;.;P;B;.;.;P;.;.
Vest4		0.74
MutPred		0.53		Loss of MoRF binding (P = 0.032);Loss of MoRF binding (P = 0.032);Loss of MoRF binding (P = 0.032);Loss of MoRF binding (P = 0.032);Loss of MoRF binding (P = 0.032);.;.;.;.;
MVP		0.98
MPC		1.8
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.54
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474724; hg19: chr1-156104630; COSMIC: COSV61543702; COSMIC: COSV61543702;