Submissions for variant NM_000183.3(HADHB):c.640G>A (p.Val214Ile)

gnomAD frequency: 0.00028  dbSNP: rs149693931

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001141296	SCV001301632	uncertain significance	Mitochondrial trifunctional protein deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001141296	SCV003264079	uncertain significance	Mitochondrial trifunctional protein deficiency	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 214 of the HADHB protein (p.Val214Ile). This variant is present in population databases (rs149693931, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HADHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 897806). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV004590106	SCV005080122	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV004629464	SCV005129055	uncertain significance	Inborn genetic diseases	2024-06-17	criteria provided, single submitter	clinical testing	The c.640G>A (p.V214I) alteration is located in exon 9 (coding exon 8) of the HADHB gene. This alteration results from a G to A substitution at nucleotide position 640, causing the valine (V) at amino acid position 214 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004756177	SCV005349326	uncertain significance	HADHB-related disorder	2024-04-12	no assertion criteria provided	clinical testing	The HADHB c.640G>A variant is predicted to result in the amino acid substitution p.Val214Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.096% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.