rs267607567

chr1-156136033-G-Achr1-156136033-G-Cchr1-156136033-G-T

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.1069G>A(p.Asp357Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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. D357E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.06

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr1-156136034-A-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP5: Variant 1-156136033-G-A is Pathogenic according to our data. Variant chr1-156136033-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1403065.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38621873).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1069G>A	p.Asp357Asn	missense_variant	6/12	ENST00000368300.9
LMNA	NM_005572.4	c.1069G>A	p.Asp357Asn	missense_variant	6/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1069G>A	p.Asp357Asn	missense_variant	6/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1069G>A	p.Asp357Asn	missense_variant	6/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 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.Asp357 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 18480576, 22224630), which suggests that this may be a clinically significant amino acid residue. 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: 1403065). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 26573435). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 357 of the LMNA protein (p.Asp357Asn). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2022

The p.D357N variant (also known as c.1069G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 1069. The aspartic acid at codon 357 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported in multiple individuals with limb girdle muscular dystrophy 1B (LGMD-1B) phenotypes; however, clinical information was limited and familial relationships were not specified (Díaz-Manera J et al. Neuromuscul. Disord. 2016;26:33-40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Benign	0.025
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	-0.087
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.32	N;.;N;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.59	T;T;T;T;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T;T;T;T
Polyphen		0.010	B;.;B;B;.;.;B;.
Vest4		0.51
MutPred		0.56		Gain of MoRF binding (P = 0.0646);Gain of MoRF binding (P = 0.0646);Gain of MoRF binding (P = 0.0646);Gain of MoRF binding (P = 0.0646);Gain of MoRF binding (P = 0.0646);.;.;.;
MVP		0.69
MPC		1.1
ClinPred		0.46	T
GERP RS		5.4
Varity_R		0.19
gMVP		0.95

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: rs267607567; hg19: chr1-156105824;