rs879253755

Positions:

• chr9-127502795-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001005373.4(LRSAM1):​c.2068T>C​(p.Cys690Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C690Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.50

Genes affected

LRSAM1 (HGNC:25135): (leucine rich repeat and sterile alpha motif containing 1) This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001005373.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 9-127502795-T-C is Pathogenic according to our data. Variant chr9-127502795-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127502795-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRSAM1	NM_001005373.4	c.2068T>C	p.Cys690Arg	missense_variant	26/26	ENST00000300417.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRSAM1	ENST00000300417.11	c.2068T>C	p.Cys690Arg	missense_variant	26/26	1	NM_001005373.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2P Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 690 of the LRSAM1 protein (p.Cys690Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant Charcot-Marie-Tooth disease (PMID: 25133958, 27353043, 33414056). ClinVar contains an entry for this variant (Variation ID: 242907). 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 LRSAM1 protein function. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	May 22, 2015	Charcot-Marie-Tooth disease type 2P has been reported by several publications to be caused by heterozygous or homozygous mutations in the LRSAM1 gene. Here we report a patient with suspicion of CMT disease type 2, harbouring a mutation which is predicted to affect the Zinc finger region of LRSAM1 protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T;T;.;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.8	H;.;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.7	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.88	P;P;P;P
Vest4		0.82
MutPred		0.71		Loss of helix (P = 0.0017);.;Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);
MVP		0.99
MPC		0.91
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.97

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: rs879253755; hg19: chr9-130265074;