NM_004744.5:c.40_41delGAinsTT

Variant names:

• chr4-154744366-GA-TT
• NM_004744.5:c.40_41delGAinsTT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM1 PM2 PP5_Moderate

The NM_004744.5(LRAT):​c.40_41delGAinsTT​(p.Glu14Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRAT NM_004744.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.33

Genes affected

LRAT (HGNC:6685): (lecithin retinol acyltransferase) The protein encoded by this gene localizes to the endoplasmic reticulum, where it catalyzes the esterification of all-trans-retinol into all-trans-retinyl ester. This reaction is an important step in vitamin A metabolism in the visual system. Mutations in this gene have been associated with early-onset severe retinal dystrophy and Leber congenital amaurosis 14. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_004744.5 (LRAT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a chain Lecithin retinol acyltransferase (size 229) in uniprot entity LRAT_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_004744.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-154744366-GA-TT is Pathogenic according to our data. Variant chr4-154744366-GA-TT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2506311.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRAT	NM_004744.5	c.40_41delGAinsTT	p.Glu14Leu	missense_variant		ENST00000336356.4	NP_004735.2
LRAT	NM_001301645.2	c.40_41delGAinsTT	p.Glu14Leu	missense_variant			NP_001288574.1
LRAT	XM_047416405.1	c.40_41delGAinsTT	p.Glu14Leu	missense_variant			XP_047272361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRAT	ENST00000336356.4	c.40_41delGAinsTT	p.Glu14Leu	missense_variant		1	NM_004744.5	ENSP00000337224.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis Pathogenic:1

May 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LRAT c.40_41delinsTT (p.Glu14Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251394 control chromosomes (gnomAD). c.40_41delinsTT has been reported in the literature in at least one homozygous individual affected with retinal dystrophy (DevBorman_2012, Scholl_2015). These data indicate that the variant maybe associated with disease. A publication reported experimental evidence evaluating an impact on protein function, demonstrating severely reduced protein levels likely due to protein instability with accelerated proteosomal degradation (Chelstowska_2017). The following publications have been ascertained in the context of this evaluation (PMID: 22570351, 26656277, 28758396, 31561851). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-155665518;