Submissions for variant NM_022915.5(MRPL44):c.467T>G (p.Leu156Arg)

dbSNP: rs143697995

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198356	SCV000251747	pathogenic	not provided	2024-08-02	criteria provided, single submitter	clinical testing	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)
UCLA Clinical Genomics Center, UCLA	RCV000054810	SCV000255451	likely pathogenic	Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency	2014-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000054810	SCV002103974	pathogenic	Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency	2022-02-10	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198356	SCV003021764	pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters MRPL44 gene expression (PMID: 23315540). 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. ClinVar contains an entry for this variant (Variation ID: 64624). 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. This variant is present in population databases (rs143697995, gnomAD 0.04%). 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).
OMIM	RCV000054810	SCV000083055	pathogenic	Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency	2013-03-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV000054810	SCV001760074	likely pathogenic	Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency		no assertion criteria provided	clinical testing