NM_000229.2:c.1210A>G

Variant names:

• chr16-67940017-T-C
• rs779114194
• NM_000229.2:c.1210A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000229.2(LCAT):​c.1210A>G​(p.Met404Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.02

Genes affected

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-67940017-T-C is Pathogenic according to our data. Variant chr16-67940017-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 626358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCAT	NM_000229.2	c.1210A>G	p.Met404Val	missense_variant	Exon 6 of 6	ENST00000264005.10	NP_000220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCAT	ENST00000264005.10	c.1210A>G	p.Met404Val	missense_variant	Exon 6 of 6	1	NM_000229.2	ENSP00000264005.5
LCAT	ENST00000570369.5	c.212A>G	p.His71Arg	missense_variant	Exon 3 of 3	2		ENSP00000459014.1
LCAT	ENST00000573538.5	n.*531A>G		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000463220.1
LCAT	ENST00000573538.5	n.*531A>G		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000463220.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461332 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726984

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 AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

LCAT deficiency Pathogenic:1

Apr 29, 2019

Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Methods: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. Results: LCAT sequencing identified rare p.V333M and p.M404V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363L variant. LCAT protein was detected in proband’s plasma, but with undetectable enzyme activity compared to control relatives. HEK-239T transfected cells with vector expression plasmids containing either p.M404V or p.V333M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Conclusion: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404V and p.V333M in LCAT gene lead to suppression of LAT enzyme activity and cause clinical features of familial LCAT deficiency. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.032
Eigen_PC	Benign	0.081
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.54
Sift	Benign	0.046	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.036	B
Vest4		0.66
MutPred		0.73		Gain of loop (P = 0.024);
MVP		0.92
MPC		0.49
ClinPred		0.80	D
GERP RS		3.4
Varity_R		0.42
gMVP		0.84

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: rs779114194; hg19: chr16-67973920;