rs267607576

chr1-156136219-G-Achr1-156136219-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP2 PP5 BP4

The NM_170707.4(LMNA):c.1163G>A(p.Arg388His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R388C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 O:1
• Conservation: PhyloP100: 2.75

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 6 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 chr1-156136219-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435771.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP5: Variant 1-156136219-G-A is Pathogenic according to our data. Variant chr1-156136219-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66790.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1}. Variant chr1-156136219-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39146098).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1163G>A	p.Arg388His	missense_variant	7/12	ENST00000368300.9
LMNA	NM_005572.4	c.1163G>A	p.Arg388His	missense_variant	7/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1163G>A	p.Arg388His	missense_variant	7/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1163G>A	p.Arg388His	missense_variant	7/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248352 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460184 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 726418

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary dilated cardiomyopathy Uncertain:2

Uncertain significance, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with histidine at codon 388 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using transfected COS7 cells suggest that this variant may impact LMNA protein activity (PMID: 20160190); however the clinical relevance of this observation is not known. This variant has been reported in a family affected with dilated cardiomyopathy, although the variant did not segregate with disease in multiple affected family members and was present in multiple unaffected family members (PMID: 18585512, 30012837). This variant has been identified in 3/248352 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg388 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28125586). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects LMNA function (PMID: 20160190). 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. ClinVar contains an entry for this variant (Variation ID: 66790). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30012837). This variant is present in population databases (rs267607576, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 388 of the LMNA protein (p.Arg388His). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2023

The p.R388H variant (also known as c.1163G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1163. The arginine at codon 388 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a family with dilated cardiomyopathy (DCM); however, it did not segregate with disease in that family and an additional alteration in RBM20 was also identified (Parks SB et al. Am Heart J, 2008 Jul;156:161-9; Li D et al. Clin Transl Sci, 2010 Jun;3:90-7). Additionally, this alteration may impact protein function; however, the physiological relevance of this finding is unclear (Cowan J et al. Circ Cardiovasc Genet, 2010 Feb;3:6-14). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostCm	Benign	0.0049
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Benign	0.028
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T;D;D;T;T;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.4	L;.;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;D;D;D;N
REVEL	Uncertain	0.49
Sift	Benign	0.10	T;T;T;T;D;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;D;T;T
Polyphen		0.035	B;.;B;B;.;.;B;.;.
Vest4		0.68
MutPred		0.45		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		0.49	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.11
gMVP		0.73

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: rs267607576; hg19: chr1-156106010;