2-223959821-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_022915.5(MRPL44):c.467T>G(p.Leu156Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_022915.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000219 AC: 55AN: 251422Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135880
GnomAD4 exome AF: 0.000357 AC: 522AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.000351 AC XY: 255AN XY: 727238
GnomAD4 genome AF: 0.000158 AC: 24AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74354
ClinVar
Submissions by phenotype
Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency Pathogenic:4
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Variant summary: MRPL44 c.467T>G (p.Leu156Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251422 control chromosomes. c.467T>G has been reported in the literature in multiple individuals. The variant has been reported in the homozygous state in siblings with hypertrophic cardiomyopathy as a leading symptom and combined respiratory complex I and IV deficiency in heart tissue and isolated complex IV deficiency in fibroblasts (Carroll_2013), in a patient with mitochondrial myopathy with second allele not specified (Florian_2015), in patients with hypertrophic cardiomyopathy and additional neurological clinical features (Distelmaier_2015), and in a patient with mitochondrial disease without other mutations in mtDNA (Legati_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrates a damaging effect of the variant including a severe reduction of MRPL44 protein levels in patient fibroblasts and altered assembly of the large ribosomal subunit and stability of 16S rRNA with complex IV deficiency, which is rescued by retroviral expression of wild-type MRPL44 (Carroll_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:2
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 156 of the MRPL44 protein (p.Leu156Arg). This variant is present in population databases (rs143697995, gnomAD 0.04%). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 23315540, 25797485). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 64624). 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 not expected to disrupt MRPL44 protein function with a negative predictive value of 80%. Studies have shown that this missense change alters MRPL44 gene expression (PMID: 23315540). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate a severe reduction of MRPL44 protein levels in patient fibroblasts and altered assembly of the large ribosomal subunit and stability of 16S rRNA with complex IV deficiency, which is rescued by retroviral expression of wild-type MRPL44 (PMID: 23315540); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23315540, 25326637, 25797485, 34426522, 33742325, 34140213, 34758253, 26001801, 34277617, 33742171, 35772644, 34732400, 26968897, 33726816, 38950860, 37628588, 38020895) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at